Amyloid beta-Protein Precursor: A single-pass type I membrane protein. It is cleaved by AMYLOID PRECURSOR PROTEIN SECRETASES to produce peptides of varying amino acid lengths. A 39-42 amino acid peptide, AMYLOID BETA-PEPTIDES is a principal component of the extracellular amyloid in SENILE PLAQUES.Amyloid beta-Peptides: Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.Amyloid: A fibrous protein complex that consists of proteins folded into a specific cross beta-pleated sheet structure. This fibrillar structure has been found as an alternative folding pattern for a variety of functional proteins. Deposits of amyloid in the form of AMYLOID PLAQUES are associated with a variety of degenerative diseases. The amyloid structure has also been found in a number of functional proteins that are unrelated to disease.Alzheimer Disease: A degenerative disease of the BRAIN characterized by the insidious onset of DEMENTIA. Impairment of MEMORY, judgment, attention span, and problem solving skills are followed by severe APRAXIAS and a global loss of cognitive abilities. The condition primarily occurs after age 60, and is marked pathologically by severe cortical atrophy and the triad of SENILE PLAQUES; NEUROFIBRILLARY TANGLES; and NEUROPIL THREADS. (From Adams et al., Principles of Neurology, 6th ed, pp1049-57)Protein PrecursorsPeptide Fragments: Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.Amyloid Precursor Protein Secretases: Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.Smilacaceae: A plant family of the order Liliales, subclass Liliidae, class Liliopsida (monocotyledon).Plaque, Amyloid: Accumulations of extracellularly deposited AMYLOID FIBRILS within tissues.Cerebral Amyloid Angiopathy: A heterogeneous group of sporadic or familial disorders characterized by AMYLOID deposits in the walls of small and medium sized blood vessels of CEREBRAL CORTEX and MENINGES. Clinical features include multiple, small lobar CEREBRAL HEMORRHAGE; cerebral ischemia (BRAIN ISCHEMIA); and CEREBRAL INFARCTION. Cerebral amyloid angiopathy is unrelated to generalized AMYLOIDOSIS. Amyloidogenic peptides in this condition are nearly always the same ones found in ALZHEIMER DISEASE. (from Kumar: Robbins and Cotran: Pathologic Basis of Disease, 7th ed., 2005)Aspartic Acid Endopeptidases: A sub-subclass of endopeptidases that depend on an ASPARTIC ACID residue for their activity.Amyloid Neuropathies: Disorders of the peripheral nervous system associated with the deposition of AMYLOID in nerve tissue. Familial, primary (nonfamilial), and secondary forms have been described. Some familial subtypes demonstrate an autosomal dominant pattern of inheritance. Clinical manifestations include sensory loss, mild weakness, autonomic dysfunction, and CARPAL TUNNEL SYNDROME. (Adams et al., Principles of Neurology, 6th ed, p1349)Moraceae: The mulberry plant family of the order Urticales, subclass Hamamelidae, class Magnoliopsida. They have milky latex and small, petalless male or female flowers.Endopeptidases: A subclass of PEPTIDE HYDROLASES that catalyze the internal cleavage of PEPTIDES or PROTEINS.Brain: The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.Iridoid Glycosides: A subclass of iridoid compounds that include a glycoside moiety, usually found at the C-1 position.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Serum Amyloid A Protein: An ACUTE PHASE REACTION protein present in low concentrations in normal sera, but found at higher concentrations in sera of older persons and in patients with AMYLOIDOSIS. It is the circulating precusor of amyloid A protein, which is found deposited in AA type AMYLOID FIBRILS.Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.Mice, Transgenic: Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Cerebral Cortex: The thin layer of GRAY MATTER on the surface of the CEREBRAL HEMISPHERES that develops from the TELENCEPHALON and folds into gyri and sulchi. It reaches its highest development in humans and is responsible for intellectual faculties and higher mental functions.Protein Processing, Post-Translational: Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.Amyloidosis: A group of sporadic, familial and/or inherited, degenerative, and infectious disease processes, linked by the common theme of abnormal protein folding and deposition of AMYLOID. As the amyloid deposits enlarge they displace normal tissue structures, causing disruption of function. Various signs and symptoms depend on the location and size of the deposits.Disease Models, Animal: Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.Islet Amyloid Polypeptide: A pancreatic beta-cell hormone that is co-secreted with INSULIN. It displays an anorectic effect on nutrient metabolism by inhibiting gastric acid secretion, gastric emptying and postprandial GLUCAGON secretion. Islet amyloid polypeptide can fold into AMYLOID FIBRILS that have been found as a major constituent of pancreatic AMYLOID DEPOSITS.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Aging: The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time.Interleukin-1beta: An interleukin-1 subtype that is synthesized as an inactive membrane-bound pro-protein. Proteolytic processing of the precursor form by CASPASE 1 results in release of the active form of interleukin-1beta from the membrane.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.Presenilin-1: Integral membrane protein of Golgi and endoplasmic reticulum. Its homodimer is an essential component of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PEPTIDES precursors. PSEN1 mutations cause early-onset ALZHEIMER DISEASE type 3 that may occur as early as 30 years of age in humans.Serum Amyloid P-Component: Amyloid P component is a small, non-fibrillar glycoprotein found in normal serum and in all amyloid deposits. It has a pentagonal (pentaxin) structure. It is an acute phase protein, modulates immunologic responses, inhibits ELASTASE, and has been suggested as an indicator of LIVER DISEASE.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Congo Red: An acid dye used in testing for hydrochloric acid in gastric contents. It is also used histologically to test for AMYLOIDOSIS.Insulysin: An enzyme the catalyzes the degradation of insulin, glucagon and other polypeptides. It is inhibited by bacitracin, chelating agents EDTA and 1,10-phenanthroline, and by thiol-blocking reagents such as N-ethylmaleimide, but not phosphoramidon. (Eur J Biochem 1994;223:1-5) EC 3.4.24.56.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Cloning, Molecular: The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.Vitellogenins: Phospholipoglycoproteins produced in the fat body of egg-laying animals such as non-mammalian VERTEBRATES; ARTHROPODS; and others. Vitellogenins are secreted into the HEMOLYMPH, and taken into the OOCYTES by receptor-mediated ENDOCYTOSIS to form the major yolk proteins, VITELLINS. Vitellogenin production is under the regulation of steroid hormones, such as ESTRADIOL and JUVENILE HORMONES in insects.Kinetics: The rate dynamics in chemical or physical systems.S100 Calcium Binding Protein beta Subunit: A calcium-binding protein that is 92 AA long, contains 2 EF-hand domains, and is concentrated mainly in GLIAL CELLS. Elevation of S100B levels in brain tissue correlates with a role in neurological disorders.Vitellogenesis: The active production and accumulation of VITELLINS (egg yolk proteins) in the non-mammalian OOCYTES from circulating precursors, VITELLOGENINS. Vitellogenesis usually begins after the first MEIOSIS and is regulated by estrogenic hormones.Peptides: Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are linear polypeptides that are normally synthesized on RIBOSOMES.beta 2-Microglobulin: An 11-kDa protein associated with the outer membrane of many cells including lymphocytes. It is the small subunit of the MHC class I molecule. Association with beta 2-microglobulin is generally required for the transport of class I heavy chains from the endoplasmic reticulum to the cell surface. Beta 2-microglobulin is present in small amounts in serum, csf, and urine of normal people, and to a much greater degree in the urine and plasma of patients with tubular proteinemia, renal failure, or kidney transplants.Transfection: The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.Presenilin-2: Integral membrane protein of Golgi and endoplasmic reticulum. Its homodimer is an essential component of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PEPTIDES precursors. PSEN2 mutations cause ALZHEIMER DISEASE type 4.ThiazolesBlotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.tau Proteins: Microtubule-associated proteins that are mainly expressed in neurons. Tau proteins constitute several isoforms and play an important role in the assembly of tubulin monomers into microtubules and in maintaining the cytoskeleton and axonal transport. Aggregation of specific sets of tau proteins in filamentous inclusions is the common feature of intraneuronal and glial fibrillar lesions (NEUROFIBRILLARY TANGLES; NEUROPIL THREADS) in numerous neurodegenerative disorders (ALZHEIMER DISEASE; TAUOPATHIES).Neurofibrillary Tangles: Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules). These double helical stacks of transverse subunits are twisted into left-handed ribbon-like filaments that likely incorporate the following proteins: (1) the intermediate filaments: medium- and high-molecular-weight neurofilaments; (2) the microtubule-associated proteins map-2 and tau; (3) actin; and (4) UBIQUITINS. As one of the hallmarks of ALZHEIMER DISEASE, the neurofibrillary tangles eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus, brain stem, and diencephalon. The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of Alzheimer disease.Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.

The amyloid precursor protein interacts with Go heterotrimeric protein within a cell compartment specialized in signal transduction. (1/2953)

The function of the beta-amyloid protein precursor (betaAPP), a transmembrane molecule involved in Alzheimer pathologies, is poorly understood. We recently reported the presence of a fraction of betaAPP in cholesterol and sphingoglycolipid-enriched microdomains (CSEM), a caveolae-like compartment specialized in signal transduction. To investigate whether betaAPP actually interferes with cell signaling, we reexamined the interaction between betaAPP and Go GTPase. In strong contrast with results obtained with reconstituted phospholipid vesicles (Okamoto et al., 1995), we find that incubating total neuronal membranes with 22C11, an antibody that recognizes an N-terminal betaAPP epitope, reduces high-affinity Go GTPase activity. This inhibition is specific of Galphao and is reproduced, in the absence of 22C11, by the addition of the betaAPP C-terminal domain but not by two distinct mutated betaAPP C-terminal domains that do not bind Galphao. This inhibition of Galphao GTPase activity by either 22C11 or wild-type betaAPP cytoplasmic domain suggests that intracellular interactions between betaAPP and Galphao could be regulated by extracellular signals. To verify whether this interaction is preserved in CSEM, we first used biochemical, immunocytochemical, and ultrastructural techniques to unambiguously confirm the colocalization of Galphao and betaAPP in CSEM. We show that inhibition of basal Galphao GTPase activity also occurs within CSEM and correlates with the coimmunoprecipitation of Galphao and betaAPP. The regulation of Galphao GTPase activity by betaAPP in a compartment specialized in signaling may have important consequences for our understanding of the physiopathological functions of betaAPP.  (+info)

Proteolytic processing of the Alzheimer's disease amyloid precursor protein within its cytoplasmic domain by caspase-like proteases. (2/2953)

Alzheimer's disease is characterized by neurodegeneration and deposition of betaA4, a peptide that is proteolytically released from the amyloid precursor protein (APP). Missense mutations in the genes coding for APP and for the polytopic membrane proteins presenilin (PS) 1 and PS2 have been linked to familial forms of early-onset Alzheimer's disease. Overexpression of presenilins, especially that of PS2, induces increased susceptibility for apoptosis that is even more pronounced in cells expressing presenilin mutants. Additionally, presenilins themselves are targets for activated caspases in apoptotic cells. When we analyzed APP in COS-7 cells overexpressing PS2, we observed proteolytic processing close to the APP carboxyl terminus. Proteolytic conversion was increased in the presence of PS2-I, which encodes one of the known PS2 pathogenic mutations. The same proteolytic processing occurred in cells treated with chemical inducers of apoptosis, suggesting a participation of activated caspases in the carboxyl-terminal truncation of APP. This was confirmed by showing that specific caspase inhibitors blocked the apoptotic conversion of APP. Sequence analysis of the APP cytosolic domain revealed a consensus motif for group III caspases ((IVL)ExD). Mutation of the corresponding Asp664 residue abolished cleavage, thereby identifying APP as a target molecule for caspase-like proteases in the pathways of programmed cellular death.  (+info)

Translation of the alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5'-untranslated region sequences. (3/2953)

The amyloid precursor protein (APP) has been associated with Alzheimer's disease (AD) because APP is processed into the beta-peptide that accumulates in amyloid plaques, and APP gene mutations can cause early onset AD. Inflammation is also associated with AD as exemplified by increased expression of interleukin-1 (IL-1) in microglia in affected areas of the AD brain. Here we demonstrate that IL-1alpha and IL-1beta increase APP synthesis by up to 6-fold in primary human astrocytes and by 15-fold in human astrocytoma cells without changing the steady-state levels of APP mRNA. A 90-nucleotide sequence in the APP gene 5'-untranslated region (5'-UTR) conferred translational regulation by IL-1alpha and IL-1beta to a chloramphenicol acetyltransferase (CAT) reporter gene. Steady-state levels of transfected APP(5'-UTR)/CAT mRNAs were unchanged, whereas both base-line and IL-1-dependent CAT protein synthesis were increased. This APP mRNA translational enhancer maps from +55 to +144 nucleotides from the 5'-cap site and is homologous to related translational control elements in the 5'-UTR of the light and and heavy ferritin genes. Enhanced translation of APP mRNA provides a mechanism by which IL-1 influences the pathogenesis of AD.  (+info)

Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. (4/2953)

Transgenic mice overexpressing different forms of amyloid precursor protein (APP), i.e. wild type or clinical mutants, displayed an essentially comparable early phenotype in terms of behavior, differential glutamatergic responses, deficits in maintenance of long term potentiation, and premature death. The cognitive impairment, demonstrated in F1 hybrids of the different APP transgenic lines, was significantly different from nontransgenic littermates as early as 3 months of age. Biochemical analysis of secreted and membrane-bound APP, C-terminal "stubs," and Abeta(40) and Abeta(42) peptides in brain indicated that no single intermediate can be responsible for the complex of phenotypic dysfunctions. As expected, the Abeta(42) levels were most prominent in APP/London transgenic mice and correlated directly with the formation of amyloid plaques in older mice of this line. Plaques were associated with immunoreactivity for hyperphosphorylated tau, eventually signaling some form of tau pathology. In conclusion, the different APP transgenic mouse lines studied display cognitive deficits and phenotypic traits early in life that dissociated in time from the formation of amyloid plaques and will be good models for both early and late neuropathological and clinical aspects of Alzheimer's disease.  (+info)

Amyloid precursor protein metabolism in fibroblasts from individuals with one, two or three copies of the amyloid precursor protein (APP) gene. (5/2953)

Protein kinase C (PKC)-activated modulation of amyloid precursor protein (APP) metabolism has been investigated in natural models of altered APP expression due to the presence of one, two or three copies of the APP gene. We show that levels of APP present in human skin fibroblasts strongly influence the effect of PKC activation of soluble APP (sAPP) release. Thus fibroblasts derived from a patient with a deletion in chromosome 21 including the APP locus (Delta21) had lower levels of both APP mRNA and cell-associated APP, and showed an exaggerated phorbol-ester-induced sAPP release, when compared with fibroblasts from control individuals. In contrast, fibroblasts from chromosome 21 trisomic Down's syndrome patients failed to show a concentration-dependent response to phorbol ester treatment. These results suggest that the levels of APP expression can affect the degree of response to PKC-mediated modulation of the metabolism of this protein.  (+info)

Regulation of beta-amyloid secretion by FE65, an amyloid protein precursor-binding protein. (6/2953)

The principal component of Alzheimer's amyloid plaques, Abeta, derives from proteolytic processing of the Alzheimer's amyloid protein precursor (APP). FE65 is a brain-enriched protein that binds to APP. Although several laboratories have characterized the APP-FE65 interaction in vitro, the possible relevance of this interaction to Alzheimer's disease has remained unclear. We demonstrate here that APP and FE65 co-localize in the endoplasmic reticulum/Golgi and possibly in endosomes. Moreover, FE65 increases translocation of APP to the cell surface, as well as both alphaAPPs and Abeta secretion. The dramatic (4-fold) FE65-dependent increase in Abeta secretion suggests that agents which inhibit the interaction of FE65 with APP might reduce Abeta secretion in the brain and therefore be useful for preventing or slowing amyloid plaque formation.  (+info)

Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. (7/2953)

Proteolytic processing of the amyloid precursor protein by beta-secretase yields A4CT (C99), which is cleaved further by the as yet unknown gamma-secretase, yielding the beta-amyloid (Abeta) peptide with 40 (Abeta40) or 42 residues (Abeta42). Because the position of gamma-secretase cleavage is crucial for the pathogenesis of Alzheimer's disease, we individually replaced all membrane-domain residues of A4CT outside the Abeta domain with phenylalanine, stably transfected the constructs in COS7 cells, and determined the effect of these mutations on the cleavage specificity of gamma-secretase (Abeta42/Abeta40 ratio). Compared with wild-type A4CT, mutations at Val-44, Ile-47, and Val-50 led to decreased Abeta42/Abeta40 ratios, whereas mutations at Thr-43, Ile-45, Val-46, Leu-49, and Met-51 led to increased Abeta42/Abeta40 ratios. A massive effect was observed for I45F (34-fold increase) making this construct important for the generation of animal models for Alzheimer's disease. Unlike the other mutations, A4CT-V44F was processed mainly to Abeta38, as determined by mass spectrometry. Our data provide a detailed model for the active site of gamma-secretase: gamma-secretase interacts with A4CT by binding to one side of the alpha-helical transmembrane domain of A4CT. Mutations in the transmembrane domain of A4CT interfere with the interaction between gamma-secretase and A4CT and, thus, alter the cleavage specificity of gamma-secretase.  (+info)

Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. (8/2953)

Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated with increased production of the amyloid beta peptide, Abeta42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, Abeta peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717V-->F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased Abeta production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of Abeta that is independent of plaque formation.  (+info)

TY - JOUR. T1 - Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency. AU - Calingasan, Noel Y.. AU - Gandy, Samuel E.. AU - Baker, Harriet. AU - Sheu, Kwan Fu Rex. AU - Smith, Jonathan D.. AU - Lamb, Bruce T.. AU - Gearhart, John D.. AU - Buxbaum, Joseph D.. AU - Harper, Clive. AU - Selkoe, Dennis J.. AU - Price, Donald L.. AU - Sisodia, Sangram S.. AU - Gibson, Gary E.. PY - 1996/9/1. Y1 - 1996/9/1. N2 - Experimental thiamine deficiency (TD) is a classical model of a nutritional deficit associated with a generalized impairment of oxidative metabolism and selective cell loss in the brain. In rats, TD-induced cell degeneration is accompanied by an accumulation of amyloid precursor protein (APP)/amyloid precursor-like protein 2 (APLP2) immunoreactivity in abnormal neurites and perikarya along the periphery of, or scattered within, the lesion. Prompted by these data and our ...
TY - JOUR. T1 - Purification and aggregation of the amyloid precursor protein intracellular domain. AU - El Ayadi, Amina. AU - Stieren, Emily S.. AU - Barral, José M.. AU - Oberhauser, Andres F.. AU - Boehning, Darren. PY - 2012/8/28. Y1 - 2012/8/28. N2 - Amyloid precursor protein (APP) is a type I transmembrane protein associated with the pathogenesis of Alzheimers disease (AD). APP is characterized by a large extracellular domain and a short cytosolic domain termed the APP intracellular domain (AICD). During maturation through the secretory pathway, APP can be cleaved by proteases termed α, β, and γ-secretases1. Sequential proteolytic cleavage of APP with β and γ-secretases leads to the production of a small proteolytic peptide, termed Aβ, which is amyloidogenic and the core constituent of senile plaques. The AICD is also liberated from the membrane after secretase processing, and through interactions with Fe65 and Tip60, can translocate to the nucleus to participate in transcription ...
Soluble amyloid precursor protein alpha (sAPPalpha) is a cleavage product of the amyloid precursor protein (APP), the etiologic agent in Alzheimers disease (AD). Reduced expression of sAPPalpha was previously found in the brains of AD patients, and it was suggested that sAPPalpha might counteract neurotoxic effects of Abeta, another APP cleavage product with enhanced abundance in Alzheimers diseased brains. However, little is known about the biological functions of sAPPalpha. Thus, efficient production of this protein is a prerequisite for further studies. The unicellular eukaryotic parasite Leishmania tarentolae has recently emerged as a promising expression system for eukaryotic proteins due to its ability to posttranslationally modify proteins combined with easy cultivation and high protein yield. Interestingly, sAPPalpha produced in L. tarentolae was biologically active and glycosylated. In contrast to nonglycosylated sAPPalpha expressed in Eschericha coli, it also featured higher ...
Variation in the susceptibility to the lethal effects of Alzheimers Amyloid Precursor Protein (APP) transgene exists among various mouse strains. Inbred FVB/N mice, expressing high levels of the transgene-encoded APP, die prior to 200 days, while inbred 129.Tg2576 mice carrying the transgene are far less susceptible. When the two strains are crossed, (FVB/Nxl29.Tg2576) FI mice survive, as does the 129.Tg2576 parent. Intercross and backcross offspring survived at rates of 60% and 35%, respectively, at 200 days signaling the presence of a polygenic trait. The goal of this study was to establish a linkage to genes affecting susceptibility to the APP transgene. The possible quantitative trait loci (QTL) were established using various genetic markers scattered throughout the genome. The presence of multiple QTLs is possible from the data obtained; however, an increased chance of type I errors (false positives) exists due to the large number of markers used for the genome scan ...
... , Authors: Dessen P. Published in: Atlas Genet Cytogenet Oncol Haematol.
AICD, the C-terminal tail generated from the proteolytic cleavage of the Amyloid Precursor Protein (APP), has been generating interest for its transcriptional modulatory roles. AICD has been hypothesized to have such a function as it is generated by a gamma-secretase-mediated regulated intramembrane proteolysis step, analogous to the generation of Notch intracellular domain (NICD), a well-known transcriptional regulator, from Notch. The AICD/Fe65/Tip60 ternary complex has been proposed as the working transcriptional regulatory complex and some of its target genes have been reported. However, our knowledge of the functions of AICD is still limited due to difficulties in detecting and manipulating the rapidly degraded peptide. Looking at AICD transcription modulation targets from a genome-wide perspective will aid our understanding of the role of AICD tremendously. To this end, AICD chromatin binding sites were investigated from a genome-wide perspective by performing Chromatin Immunoprecipitation ...
The amyloid precursor protein gene (APP) and its derivative peptides have important functions in the central nervous system. APP and Aβ fulfil criteria as neuractive peptides: presence, release and identity of action. Aβ is a peptide of 1 - 43 amino acids in length, derived from APP and the major component of the core of neuritic plaques found in Alzheimers disease. Analysis of the cDNA of Aβ revealed its origins from the larger precursor protein. There are at least four types of mRNA generated by alternative splicing of exons 7 and 8. Exon 7 encodes a 57 amino acid sequence found in the extracellular domain with major homology to the Kunitz-type of serine protease inhibitors. APP is cleaved by three secretases known as α, β, and γ secretase which act on APP at different sites producing various fragments of differing amino acid length. The γ secretase is a macromolecular enzyme complex composed of presenilin 1, 2 and other molecular constitutents essential for its function.
Background-The single spanning transmembrane amyloid precursor protein (APP) and its proteolytic product, amyloid-beta (Aβ) peptide, have been intensely studied due to their role in the pathogenesis of Alzheimers disease. However, the biological role of the secreted ectodomain of APP, which is also generated by proteolytic cleavage, is less well understood. Here, we report Tol2 red fluorescent protein (RFP) transposon gene trap integrations in the zebrafish amyloid precursor protein a (appa) and amyloid precursor-like protein 2 (aplp2) genes. The transposon integrations are predicted to disrupt the appa and aplp2 genes to primarily produce secreted ectodomains of the corresponding proteins that are fused to RFP. Results-Our results indicate the Appa-RFP and Aplp2 fusion proteins are likely secreted from the central nervous system and accumulate in the embryonic veins independent of blood flow. Conclusions-The zebrafish appa and aplp2 transposon insertion alleles will be useful for investigating the
9150PRTHomo sapiens 1Val Met Leu Lys Lys Lys Gln Tyr Thr Ser Ile His His Gly Val Val1 5 10 15Glu Val Asp Ala Ala Val Thr Pro Glu Glu Arg His Leu Ser Lys Met 20 25 30Gln Gln Asn Gly Tyr Glu Asn Pro Thr Tyr Lys Phe Phe Glu Gln Met 35 40 45Gln Asn 502134PRTHomo sapiens 2Ala Pro Lys Asn Glu Leu Val Gln Lys Phe Gln Val Tyr Tyr Leu Gly1 5 10 15Asn Val Pro Val Ala Lys Pro Val Gly Val Asp Val Ile Asn Gly Ala 20 25 30Leu Glu Ser Val Leu Ser Ser Ser Ser Arg Glu Gln Trp Thr Pro Ser 35 40 45His Val Ser Val Ala Pro Ala Thr Leu Thr Ile Leu His Gln Gln Thr 50 55 60Glu Ala Val Leu Gly Glu Cys Arg Val Arg Phe Leu Ser Phe Leu Ala65 70 75 80Val Gly Arg Asp Val His Thr Phe Ala Phe Ile Met Ala Ala Gly Pro 85 90 95Ala Ser Phe Cys Cys His Met Phe Trp Cys Glu Pro Asn Ala Ala Ser 100 105 110Leu Ser Glu Ala Val Gln Ala Ala Cys Met Leu Arg Tyr Gln Lys Cys 115 120 125Leu Asp Ala Arg Ser Gln 130325DNAArtificialPrimer APP_C50_F 3gtaccatatg gtgatgctga agaag 25432DNAArtificialPrimer APP_C50_R 4gtacaagctt ctagttctgc atctgctcaa ...
Handling of Mice. The Tg2576 mice were developed by Karen Hsaio (Hsiao et al., 1996) and licensed from the Mayo Foundation for Medical Education and Research (Rochester, MN). Male Tg2576 transgenic mice were bred to normal C57BL6/SJL females at the Bristol-Myers Squibb facility in Wallingford, CT. Mice were housed with a 6:00 AM to 6:00 PM light/dark cycle and allowed free access to food and water. Both male and female mice were used in these studies, and although no differences in Aβ were observed between them, only one sex was used in a single study. Young Tg2576 mice were used between 3 and 6 months of age, whereas aged animals were used at 14 to 17 months. BMS-299897 was synthesized by the Medicinal Chemistry groups of SIBIA Neurosciences, Inc. (now Merck Research Laboratories, San Diego, CA) and Bristol-Myers Squibb. Animals were dosed by oral gavage in a volume of 6 ml/kg in polyethylene glycol, average molecular weight of 400, or a vehicle consisting of 10% propylene glycol, 7.5% ...
To address the substrate requirements of BACE-IgG, we designed three peptide substrates, each containing 30 amino acids, extending from P21 to P9 to span the β-secretase cleavage site. These peptides represent: (i) APPwt; (ii) APPsw; and (iii) the MV substitution (P1 changed from Met → Val). In intact cells, endogenous β-secretase cleaves APPsw much better than APPwt, but the MV mutant is not cleaved (22). Pure BACE-IgG cleaves the pure wt peptide with a specific activity of approximately 9 nmol/min/mg, demonstrating that BACE acts as a protease (Fig. 8B). We detect only one cleavage and this is at the correct Asp1 site (24). As expected for β-secretase, the specific activity of BACE-IgG for the Swedish substrate is much higher than for the wt substrate, whereas cleavage of the MV mutant is not detectable at all (Fig. 8B).. Experiments with intact cells suggest that β-secretase has an acidic pH optimum (14, 15). Indeed, a pH titration of BACE activity shows an optimum at pH 4.5 for both ...
TY - JOUR. T1 - Presenilin 1 mutations increase amyloid precursor protein production and proteolysis in Xenopus laevis oocytes. AU - Heyn, Sietske N.. AU - Vulliet, Philip R. PY - 2001/6/22. Y1 - 2001/6/22. N2 - Recent findings suggest that Presenilin 1 (PS1) mutations play a major role in the development of Alzheimers disease (AD) by increasing the production of the beta amyloid peptide (Aβ). The exact mechanism whereby mutations in PS1 lead to this effect is not clear. To examine the question of how PS1 might be involved in amyloid precursor protein (APP) processing, we constructed a chimera of human APP695 fused at the C-terminal to enhanced green fluorescent protein (EGFP). This construct was injected into Xenopus laevis oocytes in the presence of wild type PS1 or one of three PS1 mutations associated with AD. The cellular location of the APP695-EGFP construct was examined by fluorescent confocal microscopy. In addition, membrane fractions of oocytes expressing APP695-EGFP in the presence ...
In mammals, many of the proteins taking part in the complex network of interactions centred at the cytosolic domain of APP belong to gene families. This is in fact the case for APP-like genes, as well as for Fe65- and X11-like members. APP-like gene family members have been analysed in depth, in mammals, by reverse genetics. However, their redundancy prevented the generation of clear phenotypes from murine knock-outs of the single APP, APLP1 or APLP2 genes ( Zheng et al., 1995; von Koch et al., 1997; Heber et al., 2000), whereas mice with combined knock-outs displayed severe phenotypes, dying early and post-natally. Taken together, the functions of these genes have been proposed as essential and partially redundant in mammals ( Heber et al., 2000). A similar phenotype, although not strictly predictable, might occur if reverse genetic approaches were used with the mammalian Fe65 gene family members. This was one of the reasons that prompted us to investigate potential Fe65-like genes in the ...
Recombinant Human Amyloid Precursor Protein Protein fragment datasheet (ab124588). Abcam offers quality products including antibodies, assays and other…
Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, Greengard P, Kirino Y, Nairn AC, Suzuki T. Neuron-specific phosphorylation of Alzheimers beta-amyloid precursor protein by cyclin-dependent kinase 5 ...
Numerous transmembrane proteins, including the blood pressure regulating angiotensin converting enzyme (ACE) and the Alzheimers disease amyloid precursor protein (APP), are proteolytically shed from the plasma membrane by metalloproteases. We have used an antisense oligonucleotide (ASO) approach to delineate the role of ADAM10 and tumour necrosis factor-α converting enzyme (TACE; ADAM17) in the ectodomain shedding of ACE and APP from human SH-SY5Y cells. Although the ADAM10 ASO and TACE ASO significantly reduced (, 81%) their respective mRNA levels and reduced the α-secretase shedding of APP by 60% and 30%, respectively, neither ASO reduced the shedding of ACE. The mercurial compound 4-aminophenylmercuric acetate (APMA) stimulated the shedding of ACE but not of APP. The APMA-stimulated secretase cleaved ACE at the same Arg-Ser bond in the juxtamembrane stalk as the constitutive secretase but was more sensitive to inhibition by a hydroxamate-based compound. The APMA-activated shedding of ACE ...
TY - JOUR. T1 - A novel γ-secretase assay based on detection of the putative C-terminal fragment-γ of amyloid β protein precursor. AU - Pinnix, Inga. AU - Musunuru, Usha. AU - Tun, Han W. AU - Sridharan, Arati. AU - Golde, Todd. AU - Eckman, Christopher. AU - Ziani-Cherif, Chewki. AU - Onstead, Luisa. AU - Sambamurti, Kumar. PY - 2001/1/5. Y1 - 2001/1/5. N2 - Alzheimers disease is characterized by the deposits of the 4-kDa amyloid β peptide (Aβ). The Aβ protein precursor (APP) is cleaved by β-secretase to generate a C-terminal fragment, CTFβ, which in turn is cleaved by γ-secretase to generate Aβ. Alternative cleavage of the APP by α-secretase at Aβ16/17 generates the C-terminal fragment, CTFα. In addition to Aβ, endoproteolytic cleavage of CTFα and CTFβ by γ-secretase should yield a C-terminal fragment of 57-59 residues (CTFγ). However, CTFγ has not yet been reported in either brain or cell lysates, presumably due to its instability in vivo. We detected the in vitro ...
As has been described in naturally occurring CAA (1, 5), vascular amyloid deposition in APP23 mice is most frequently found in arteries/arterioles and occurs most often in vessels outside the brain parenchyma proper (e.g., pia, fissures). The arterial predilection suggests that an anatomical difference between arteries and veins (e.g., presence of significant amounts of smooth muscle) could contribute to the development of CAA. Indeed, it has been hypothesized that Aβ is deposited by vascular smooth muscle cells and/or perivascular microglia, and APP expression and Aβ production by vascular cells have been well documented (22, 23). These reports and the observation that vessels apart from the neuropil are more often affected strongly implicate local production or circulating Aβ as an important source, although these hypotheses fail to explain the exclusive localization of CAA to cerebral vessels. In the present study, through examination of APP transgenic mice on an App-null background, we ...
The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs). Senescence caused a decrease in APP expression thereby resulting in reduced secretion of soluble APPα (sAPPα). In contrast, β-site APP cleaving enzyme (BACE1) expression and production of amyloid β (Aβ)40 were increased in senescent endothelium. Importantly, in senescent human BMECs, treatment with BACE1 inhibitor IV inhibited Aβ generation and increased sAPPα production by enhancing a disintegrin and metalloprotease (ADAM)10 expression. Furthermore, Ang II impaired expression of ADAM10 and significantly reduced generation of sAPPα in senescent human BMECs. This inhibitory effect of Ang II was prevented by treatment with BACE1 inhibitor IV. Our results suggest that impairment of α-processing and shift to amyloidogenic pathway of APP contribute to endothelial dysfunction induced by
APP (Amyloid Precursor Protein), eFluor 570, clone: 22C11, eBioscience™ 100μg; eFluor 570 APP (Amyloid Precursor Protein), eFluor 570, clone: 22C11,...
As with industrious employees, it is hard to spur greater productivity in an enzyme by simply cracking the whip. However, clearing distractions might do the trick. Taking this strategy into an Alzheimer disease mouse model, scientists have boosted the activity of an Aβ-degrading enzyme by reducing levels of an endogenous inhibitor. The enzyme, cathepsin B (CatB), caught the attention of Li Gan at the Gladstone Institute of Neurological Disease in San Francisco several years ago when it appeared to prevent buildup of amyloid plaques in the brains of AD mice overexpressing mutant human amyloid precursor protein (APP). In the October 23 Neuron, Gan and colleagues now report that APP mice lacking cystatin C (CysC)-an inhibitor of cysteine proteases including CatB-have lower soluble Aβ levels and reduced Aβ-associated deficits in cognition, behavior, and synaptic plasticity compared to APP/CysC+/+ mice. By crossing the animals onto a CatB-null background, they show that these benefits depend on ...
Abnormal production and accumulation of amyloid-β peptide (Aβ) plays a major role in the pathogenesis of Alzheimers disease (AD). β-secretase (BACE1) is responsible for the cleavage at the β-site in amyloid β protein precursor (AβPP/APP) to generate
Increased amyloid-β (Aβ) load in the brain, neurite degeneration, neuronal loss, and decreased levels of several neurotrophins are among the characteristics of Alzheimers disease (AD). Generation of Aβ occurs when the amyloid precursor protein (APP) is proteolytically processed by β- and γ-secretases in the amyloidogenic pathway. However, Aβ formation is prevented if APP is cleaved by α- and γ- secretases in the non-amyloidogenic pathway. The normal function of APP is still not fully known. It seems clear that the different fragments that are produced during proteolytic processing have different bioactive properties. APP and its metabolites have been implicated in neurite outgrowth, synaptogenesis, cell adhesion, neuroprotection and apoptosis.. The aim of this thesis was to investigate how neurotrophic factors affect the synthesis and processing of APP and its two mammalian paralogues the APP-like protein-1 and-2 (APLP1 and APLP2). We also wanted to determine how the expression levels ...
TY - JOUR. T1 - Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of lysine 688. AU - Ayadi, Amina El. AU - Stieren, Emily S.. AU - Barral, José M.. AU - Boehning, Darren. PY - 2012/8/14. Y1 - 2012/8/14. N2 - The pathogenesis of Alzheimers disease (AD) is associated with proteolytic processing of the amyloid precursor protein (APP) to an amyloidogenic peptide termed Aβ. Although mutations in APP and the secretase enzymes that mediate its processing are known to result in familial forms of AD, the mechanisms underlying the more common sporadic forms of the disease are still unclear. Evidence suggests that the susceptibility of APP to amyloidogenic processing is related to its intracellular localization, and that secretase-independent degradation may prevent the formation of cytotoxic peptide fragments. Recently, single nucleotide polymorphisms in the UBQLN1 gene have been linked to late-onset AD, and its protein product, ...
Amyloid beta precursor protein gene (ABPP) encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a…
TY - JOUR. T1 - Galectin 3- binding protein suppresses amyloid-β production by modulating β-cleavage of amyloid precursor protein. AU - Seki, Tsuneyoshi. AU - Kanagawa, Motoi. AU - Kobayashi, Kazuhiro. AU - Kowa, Hisatomo. AU - Yahata, Naoki. AU - Maruyama, Kei. AU - Iwata, Nobuhisa. AU - Inoue, Haruhisa. AU - Toda, Tatsushi. PY - 2020/3/13. Y1 - 2020/3/13. N2 - Alzheimers disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of β-amyloid (Aβ) peptides. Aβ is produced from amyloid precursor protein (APP) that is sequentially cleaved by β- and γ-secretases. Therefore, APP processing has been a target in therapeutic strategies for managing AD; however, no effective treatment of AD patients is currently available. Here, to identify endogenous factors that modulate Aβ production, we performed a gene microarray- based transcriptome analysis of neuronal cells derived from human induced pluripotent stem cells, because Aβ production in these ...
Insoluble beta-amyloid deposits in Alzheimers disease (AD) brain are proteolytically derived from the membrane bound amyloid precursor protein (APP). The APP gene is differentially spliced to produce isoforms that can be classified into those containing a Kunitz-type serine protease inhibitor domain (K(+), APP(751), APP(770), APRP(365) and APRP(563)), and those without (K(-), APP(695) and APP(714)). Given the hypothesis that Abeta is a result of aberrant catabolism of APP, differential expression of mRNA isoforms containing protease inhibitors might play an active role in the pathology of AD. We took 513 cerebral cortex samples from 90 AD and 81 control brains and quantified the mRNA isoforms of APP with TaqMan real-time RT-PCR. After adjustment for age at death, brain pH and gender we found a change in the ratio of KPI(+) to KPI(-) mRNA isoforms of APP. Three separate probes, designed to recognise only KPI(+) mRNA species, gave increases of between 28% and 50% in AD brains relative to controls ...
Antimicrobial peptides are important effector molecules of the innate immune system. Here, we describe that peptides derived from the heparin-binding disulfide-constrained loop region of human beta-amyloid precursor protein are antimicrobial. The peptides investigated were linear and cyclic forms of NWCKRGRKQCKTHPH (NWC15) as well as the cyclic form comprising the C-terminal hydrophobic amino acid extension FVIPY (NWCKRGRKQCKTHPHFVIPY; NWC20c). Compared with the benchmark antimicrobial peptide LL-37, these peptides efficiently killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Staphylococcus aureus and Bacillus subtilis, and the fungi Candida albicans and Candida parapsilosis. Correspondingly, fluorescence and electron microscopy demonstrated that the peptides caused defects in bacterial membranes. Analogously, the peptides permeabilised negatively charged liposomes. Despite their bactericidal effect, the peptides displayed very limited hemolytic ...
In a 2014 scientific study, researchers have discovered strong evidence of the therapeutic effects of THC found in cannabis, in regards to reversing the brain damage associated with Alzheimers Disease. The results clearly are in favor of low-dose, monitored use of cannabis to lower the levels of amyloid-beta precursor proteins, characteristic of this health problem.. Amyloid-beta precursor proteins are large membrane proteins that support neural health, growth, and repair. Due to the natural aging process and the presence of inflammation, a corrupted version of these proteins may begin to produce, destroying neurons and consequently, the memories, thinking process, and even the personality of the Alzheimers patient.. If THC successfully lowers the level of the corrupted amyloid-beta precursor proteins, does this mean that Alzheimers Disease can be completely reversed? Scientists do not yet have clear-cut and straightforward answers to this important question. Even though the political and ...
The amyloid precursor protein (APP) protein has been in the limelight of research on Alzheimer´s disease (AD) pathogenesis because its proteolytic processing gives rise to the neurotoxic amyloid β (Aβ) peptide, the main constituent of amyloid plaques in the brains of AD patients. APP is sequentially processed by at least three different proteases termed α-, β-, and γ-secretases. The proteolytic processing of APP can be divided into two different pathways, the non-amyloidogenic and the amyloidogenic. Whether APP is processed by the non-amyloidogenic or the amyloidogenic pathway is highly dependent on co-localization of APP with the different processing enzymes. Hence, understanding the mechanism underlying regulation of APP trafficking and its related secretases is of great importance in our understanding of AD and AD pathogenesis. The aim of this thesis was to study the processing and trafficking of APP, how it may be regulated by the interaction with the adaptor protein, Fe65, and by a ...
The Tg2576 mouse, which carries the Swedish mutant form of human beta-amyloid precursor protein (hAPP(swe)), develops Alzheimers Disease (AD)-like phenotype (synaptic pathology, cognitive impairment and beta amyloid -A beta-plaques.) in the absence of significant neuronal loss. We have analyzed the hippocampal proteome of Tg2576, focusing on changes at 7 months of age, when A beta levels begin to increase but cognitive symptoms are still not evident, and at 16 months, when most AD-like features are manifested. Proteins differentially expressed with respect to wild-type animals were grouped according to their biological function and assessed in the context of AD. Metabolic enzymes, propionyl-CoA carboxylase, which has not been previously related to AD, and glutamine synthetase, which is a key enzyme for ammonium removal, were among deregulated proteins. Mitochondria of young animals have to cope with the metabolic stress and elevated ATP demand caused by overexpression of hAPP(swe). ...
We have shown that the expression of a number of protective genes and a protective pathway culminating in Bad phosphorylation are increased in mice that overexpress APPSw and have no neuronal loss. Increased levels of IGF-2 mRNA and protein correspond to increased activation of the IGF-1 receptor, activation of Akt and Erk1/2, and phosphorylation of Bad in APPSw mice. The increased expression of TTR and IGF-2 as well as increased phospho-Bad staining in hippocampal neurons was consistent in both preplaque (6 months) and postplaque (12 months) Tg2576 mice. Other conditions, such as the presence of a human tau gene, may be necessary for complete AD pathology. However, taken together, these data imply that the lack of neurodegeneration in APPSw mice is a result of the activation of known cell survival pathways associated with the overexpression of APPSw.. Transthyretin has been shown to bind Aβ and inhibit Aβ aggregation (Schwarzman et al., 1994). In human AD patients the concentration of TTR is ...
What are the main advantages and drawbacks of the model system you have used as it relates to the disease you are investigating?. The problems with first-generation Aβ precursor protein (APP) transgenic mice have been well established. In short, many AD mouse models achieve elevated Aβ by overexpressing APP, and then relying upon familial AD mutations to overexpress Aβ. In AD, APP expression is similar between AD and control subjects, with mutations only elevating Aβ40 and Aβ42. The effects of APP overexpression have been studied in mice, and the phenotype is strikingly similar to what one would expect to find as a result of AD pathology, both in terms of behaviour and molecular biology of excitatory synapses. Hence, dissociating the effect of Aβ from APP overexpression has been challenging, especially when many researchers use wild-type and not APP-overexpressing mice as controls.. The new generation of mice called AppNL-G-F created by Saito and colleagues (co-authors) express APP at ...
Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-β 1-42 peptide (Aβ1-42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Aβ1-42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APPswe) of Alzheimers disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid β precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered ...
Production of soluble amyloid peptide precursor (APP) and amyloid peptide (A beta) was measured in CHO cells transfected by the wild-type APP 695 cDNA sequence or by the same sequence carrying missense mutations associated with familial Alzheimers disease in Sweden. Deletion of the C-terminal domain of the protein corresponding to residues 654 to 695 of APP 695 not only inhibited very significantly the internalization of APP at 37 degrees C, but also led to the secretion of an uncleaved APP in the culture medium of CHO cells. This deletion did not affect A beta production from the Swedish APP but was able to inhibit the production of the wild-type APP. These results demonstrate that, in CHO cells, the internalization of the wild-type APP is needed for A beta production, while the production of the amyloid peptide from Swedish APP is independent of the internalization process. ...
Background: Amyloid- neurotoxicity depends on the specificity of the proteolytic cleavage of the amyloid precursor protein (APP) transmembrane domain. Results: The APP transmembrane -helix is straight in a biological membrane bilayer. Conclusion: The flexibility of APP is key for adapting to the lipid environment and modulating proteolytic processing by -secretase. Significance: The dynamic characterization of APP is expected to rationalize the design of -secretase modulators. The amyloid precursor protein (APP) is a widely expressed type I transmembrane (TM) glycoprotein present at the neuronal synapse. The proteolytic cleavage by -secretase of its C-terminal fragment produces amyloid- (A) peptides of different lengths, the deposition of which is an early indicator of Alzheimer disease. At present, there is no consensus on the conformation of the APP-TM domain at the biological membrane. Although structures have been determined by NMR in detergent micelles, their conformation is markedly ...
Halim A., Brinkmalm G., Ruetschi U., Westman-Brinkmalm A., Portelius E., Zetterberg H., Blennow K., Larson G., Nilsson J.. The proteolytic processing of human amyloid precursor protein (APP) into shorter aggregating amyloid β (Aβ)-peptides, e.g., Aβ1-42, is considered a critical step in the pathogenesis of Alzheimers disease (AD). Although APP is a well-known membrane glycoprotein carrying both N- and O-glycans, nothing is known about the occurrence of released APP/Aβ glycopeptides in cerebrospinal fluid (CSF). We used the 6E10 antibody and immunopurified Aβ peptides and glycopeptides from CSF samples and then liquid chromatography-tandem mass spectrometry for structural analysis using collision-induced dissociation and electron capture dissociation. In addition to 33 unglycosylated APP/Aβ peptides, we identified 37 APP/Aβ glycopeptides with sialylated core 1 like O-glycans attached to Thr(-39, -21, -20, and -13), in a series of APP/AβX-15 glycopeptides, where X was -63, -57, -52, and ...
The primary constituent of the amyloid plaque, beta-amyloid (Abeta), is thought to be the causal "toxic moiety" of Alzheimers disease. However, despite much work focused on both Abeta and its parent protein, amyloid precursor protein (APP), the functional roles of APP and its cleavage products remain to be fully elucidated. Protein-protein interaction networks can provide insight into protein function, however, high-throughput data often report false positives and are in frequent disagreement with low-throughput experiments. Moreover, the complexity of the CNS is likely to be under represented in such databases. Therefore, we curated the published work characterizing both APP and Abeta to create a protein interaction network of APP and its proteolytic cleavage products, with annotation, where possible, to the level of APP binding domain and isoform. This is the first time that an interactome has been refined to domain level, essential for the interpretation of APP due to the presence of ...
Alzheimers disease (AD) is a progressive neurodegenerative disorder. Amyloid precursor protein (APP) processing and the subsequent generation of amyloid β (Aβ) are central to the pathogenesis of AD, as soluble, oligomeric Aβ peptides are thought to be the toxic species driving disease progression. Flavonoids, a group of dietary polyphenols, have been shown to possess cognitive health benefits. Epidemiological evidence suggests they could play a role in risk reduction in dementia. In vitro and in vivo reports suggest flavonoids can modulate APP metabolism and Aβ production, although the most effective compounds and the underlying mechanism of action remain unclear. This study identified select flavonoids that were able to reduce amyloidogenic processing in primary cortical neurons at physiologically relevant concentrations. An APP-Gal4 gene reporter assay was characterised for identification of modulators of APP processing in primary neurons. It was tested under physiological conditions, in ...
These transgenic mice exhibit increasing expression of human amyloid beta precursor protein in the cortex, hippocampus, brain stem, and cerebellum with age. This mutant mouse strain may be useful in studies of Alzheimers disease.
Mô tả: Membrane-type 5-matrix metalloproteinase (MT5-MMP) is a proteinase mainly expressed in the nervous system with emerging roles in brain pathophysiology. The implication of MT5-MMP in Alzheimers disease (AD), notably its interplay with the amyloidogenic process, remains elusive. Accordingly, we crossed the genetically engineered 5xFAD mouse model of AD with MT5-MMP-deficient mice and examined the impact of MT5-MMP deficiency in bigenic 5xFAD/MT5-MMP(-/-) mice. At early stages (4 months) of the pathology, the levels of amyloid beta peptide (Aβ) and its amyloid precursor protein (APP) C-terminal fragment C99 were largely reduced in the cortex and hippocampus of 5xFAD/MT5-MMP(-/-), compared to 5xFAD mice. Reduced amyloidosis in bigenic mice was concomitant with decreased glial reactivity and interleukin-1β (IL-1β) levels, and the preservation of long-term potentiation (LTP) and spatial learning, without changes in the activity of α-, β- and γ-secretases. The positive impact of... ...
Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export. APP is best known as the precursor molecule whose proteolysis generates beta amyloid (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimers disease patients. APP is an ancient and highly conserved protein. In humans, the gene for APP is located on chromosome 21 and contains 18 exons spanning 290 kilobases. Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 639 to 770 amino acids, with certain isoforms preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimers disease. Homologous proteins have been ...
In conclusion, we provide evidence for the first time that polymorphisms located in the 3UTR of hAPP may affect its expression, at least in the experimental conditions tested here. Indeed, we show that two AD-specific 3UTR variants previously identified by Bettens and colleagues [20] affect the modulating activity of miR-147 and miR-20a on the expression of APP. SNP T171C decreases the ability of miR-147 to down-regulate APP, theoretically leading to increased APP and Aβ production. On the other hand, SNP A454G increases the effect of miR-20a, suggesting that APP expression is reduced in these patients. Although these data seem to contradict with the main hypothesis that increased APP levels lead to AD, some reports indicate that decreasing the APP levels might have deleterious consequences in the brain [24, 25]. Another possibility is that miR-20a levels (or function) vary depending on brain region or disease state, therefore only locally affecting APP. In line with this hypothesis, our ...
Supplementary MaterialsMultimedia component 1 mmc1. log-rank check. The variables with significantly less than 0.05 in univariate analyses were contained in the multivariable Cox analysis. Statistical analyses had been performed with GraphPad edition 6.0 or SPSS 20.0. A significantly less than 0.05 was considered significant statistically, and everything statistical exams were two-sided. The facts for cell reagents and lines, RNA removal and qPCR evaluation, Apoptosis evaluation, anoikis assay, gentle agar colony development assay, Chromatin immunoprecipitation (ChIP) assay and Luciferase promoter assay are referred to in the Supplementary Ribitol (Adonitol) Components and strategies. 3.?Outcomes 3.1. DGAT2 is certainly upregulated in HFD-treated mice and metastatic GC sufferers We first looked into whether HFD prompts peritoneal metastasis worth are shown. (D) qPCR evaluation of DGAT2 appearance in BGC823 and HGC27?cells after siRNA-mediated knockdown of C/EBP cultured with 200?M oleic acidity. ...
Complete information for APBB1IP gene (Protein Coding), Amyloid Beta Precursor Protein Binding Family B Member 1 Interacting Protein, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Complete information for APBB1 gene (Protein Coding), Amyloid Beta Precursor Protein Binding Family B Member 1, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
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1AQC: Sequence-specific recognition of the internalization motif of the Alzheimers amyloid precursor protein by the X11 PTB domain.
... (APP) is a type-I transmembrane protein enriched in neuronal tissues that undergoes sequential proteolytic processing through two distinct pathways. One pathway generate non-pathogenic molecules while the other generates Amyloid β (Aβ), which accumulates resulting in neurotoxicity and is associated with Alzheimers disease. BioLegend provides an extensive collection of antibodies and reagents for the study of APP and Aβ. BioLegend develops and manufactures world-class, cutting-edge immunological reagents for biomedical research, offered at an outstanding value.
This study demonstrates that pre-plaque TgCRND8 mice exhibit early behavioral alterations only in a subset of hippocampal-dependent tasks associated with drastic deficits in hippocampal inhibitory networks and altered γ oscillations. Strikingly, we showed that different APP metabolites were likely responsible for specific memory deficits in two different tasks. Overall, our study supports the current hypothesis that Aβ is unable to account for all aspects of cognitive impairments in AD, highlighting the complexity of the amyloid pathology.. As the field inches toward early detection of AD to provide precocious treatment (34), it is critical to assess the respective role of each APP fragment in the earliest stage of the disease. Hence, we focused our work on young adult TgCRND8 mice, a well-characterized mouse model of AD-like amyloid pathology (22). In this mouse model, robust expression of Aβ begins around 10 weeks of age, and amyloid deposits appear at 3 months (22). Therefore, we ...
... skeletal muscle-specific Ca2+/calmodulin-dependent protein kinase; Akt; Beta-amyloid precursor protein (betaAPP); Huntingtin. ... For example, GAPDH interactions with beta-amyloid precursor protein (betaAPP) could interfere with its function regarding the ... GAPDH participates in a number of biological functions through its protein-protein interactions with: tubulin to facilitate ... where it ubiquitinates and degrades nuclear proteins during nitrosative stress conditions; GAPDH's competitor of Siah protein ...
Chen Y, Bodles AM (2007). "Amyloid precursor protein modulates beta-catenin degradation". Journal of Neuroinflammation. 4: 29. ... Beta-catenin-interacting protein 1 is a protein that is encoded in humans by the CTNNBIP1 gene. The protein encoded by this ... Sharma M, Henderson BR (2007). "IQ-domain GTPase-activating protein 1 regulates beta-catenin at membrane ruffles and its role ... 2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3 (1): 89. doi: ...
Amyloid beta A4 precursor protein-binding family B member 1-interacting protein (APBB1IP), also known as APBB1-interacting ... amyloid beta (A4) precursor protein-binding". Inagaki T, Suzuki S, Miyamoto T, Takeda T, Yamashita K, Komatsu A, Yamauchi K, ... 1997). "The WW domain of neural protein FE65 interacts with proline-rich motifs in Mena, the mammalian homolog of Drosophila ... protein 1 or Rap1-GTP-interacting adapter molecule (RIAM) is a protein that in humans is encoded by the APBB1IP gene. GRCh38: ...
APP is an Amyloid beta A4 precursor protein. It is suspected to have a major role in cognitive difficulties. Another gene, ETS2 ... Online Mendelian Inheritance in Man (OMIM) AMYLOID BETA A4 PRECURSOR PROTEIN; APP -104760, gene located at 21q21. Retrieved on ... Down syndrome individuals to develop Alzheimer's pathology is the gene that encodes the precursor of the amyloid protein. ... Neurofibrillary tangles and amyloid plaques are commonly found in both Down syndrome and Alzheimer's individuals. Layer II of ...
JAFFE, AB; et.al (1994). "ESTROGEN REGULATES METABOLISM OF ALZHEIMER AMYLOID-BETA PRECURSOR PROTEIN". Journal of Biological ... Amyloid precursor protein (APP) proteolysis is fundamental for production of Aβ peptides implicated in AD pathology. By using a ... Amyloid plaques formed by amyloid-β (Aβ) deposition and neurofibrillary tangles formed by tau protein phosphorylation are ... The role of estrogens is mostly mediated by two nuclear receptors (ER alpha and ER beta) and a membrane-associated G-protein ( ...
... Amyloid beta (A4) precursor-like protein 2". Leach R, Ko M, Krawetz SA (1999). "Assignment of amyloid-precursor-like ... "Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein". Proceedings ... "APLP2 - Amyloid-like protein 2 precursor - Homo sapiens (Human) - APLP2 gene & protein". www.uniprot.org. Retrieved 2016-10-03 ... APLP2 is part of a family of mammalian membrane proteins along with APLP1 and amyloid precursor protein (APP). Since APP plays ...
Beta-amyloid is a small piece of a larger protein called the amyloid precursor protein (APP). Once APP is activated it is cut ... Mutations to the amyloid beta A4 precursor protein (APP) located on the long arm of chromosome 21 (21q21.3) cause familial ... "Increased β-amyloid release and levels of amyloid precursor protein (APP) in fibroblast cell lines from family members with the ... suggesting that the Asn141Ile mutation alters amyloid precursor protein (APP) metabolism causing an increased rate of protein ...
Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis, Science. 1990 June 1;248(4959):1120-2 ... in 1993 she and three other scientists were awarded the American Potamkin Prize for their work on the amyloid precursor protein ...
Kirfel G, Borm B, Rigort A, Herzog V (2002). "The secretory beta-amyloid precursor protein is a motogen for human epidermal ... This protein may be a target of neurotoxic beta-amyloid peptide, and may mediate cellular vulnerability to beta-amyloid peptide ... The protein encoded by this gene is a beta-amyloid peptide-binding protein. It contains a structural module related to that of ... "Beta-amyloid peptide binding protein does not couple to G protein in a heterologous Xenopus expression system". J. Neurosci. ...
The protein encoded by this gene binds to the beta-amyloid precursor protein. Beta-amyloid precursor protein is a cell surface ... APPBP1 (Amyloid Precursor Protein-Binding Protein 1) binds to the Amyloid Precursor Protein (APP) carboxy terminal domain. ... APPBP1 amyloid beta precursor protein binding protein 1". Chen Y, McPhie DL, Hirschberg J, Neve RL (March 2000). "The amyloid ... APPBP1 was first cloned and identified by its interaction with the C-terminus of beta-amyloid protein precursor (precursor to ...
"Reelin in plaques of beta-amyloid precursor protein and presenilin-1 double-transgenic mice". Neuroscience Letters. 316 (3): ... "Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein". The ... Reelin has been shown to interact with amyloid precursor protein, and, according to one in-vitro study, is able to counteract ... "Interaction of reelin with amyloid precursor protein promotes neurite outgrowth". The Journal of Neuroscience. 29 (23): 7459-73 ...
2006). The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 440(7083): ... Absence of Pin1 activity in humans has also been implicated in the folding and processing of the amyloid precursor protein, ... Parvulin, a 92-amino acid protein discovered in E. coli in 1994, is the smallest known protein with prolyl isomerase activity, ... 2000). Proline isomerizarion and its catalysis in protein folding. In Mechanisms of Protein Folding 2nd ed. Ed. RH Pain. ...
... enhance the X11-like protein-mediated stabilization of amyloid beta-protein precursor metabolism". The Journal of Biological ... enhance the X11-like protein-mediated stabilization of amyloid beta-protein precursor metabolism". The Journal of Biological ... "Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation". The ... "Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation". The ...
"Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients". Science. 279 (5348): ... Dennissen FJ, Kholod N, Steinbusch HW, Van Leeuwen FW (2010). "Misframed proteins and neurodegeneration: a novel view on ...
2002). "Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc". J. Biol ... SHC-transforming protein 3 is a protein that in humans is encoded by the SHC3 gene. SHC3 has been shown to interact with RICS ... Menegon A; Leoni C; Benfenati F; Valtorta F (1997). "Tat protein from HIV-1 activates MAP kinase in granular neurons and glial ... 1996). "A mammalian adaptor protein with conserved Src homology 2 and phosphotyrosine-binding domains is related to Shc and is ...
"Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation". ... factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor". ... "Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline". JAMA. 283 (12): 1571-1577. doi ... In Alzheimer disease, Buxbaum has conducted several cell-biological and patient-based analyses of APP and A-beta and he and his ...
Matsumoto A, Itoh K, Matsumoto R (2000). "A novel carboxypeptidase B that processes native beta-amyloid precursor protein is ... Mosnier LO, Meijers JC, Bouma BN (2002). "The role of protein S in the activation of thrombin activatable fibrinolysis ... Mosnier LO, Elisen MG, Bouma BN, Meijers JC (2002). "Protein C inhibitor regulates the thrombin-thrombomodulin complex in the ... After thrombin activation, the mature protein downregulates fibrinolysis. Polymorphisms have been described for this gene and ...
"Regional brain cytochrome oxidase activity in beta-amyloid precursor protein transgenic mice with the Swedish mutation". ... Aledo JC, Valverde H, Ruiz-Camacho M, Morilla L, López FD (2014). "Protein-Protein Interfaces from Cytochrome c Oxidase I ... The complex is a large integral membrane protein composed of several metal prosthetic sites and 14 protein subunits in mammals ... Soltys BJ, Gupta RS (1999). "Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from ...
Ohsawa I, Takamura C, Kohsaka S (Mar 2001). "Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein and ... FBLN1 has been shown to interact with: NOV/CCN3, amyloid precursor protein, entactin, fibrinogen, and fibronectin. ... a novel protein that interacts with the fibronectin receptor beta subunit cytoplasmic domain". Cell. 58 (4): 623-9. doi:10.1016 ... Pan TC, Kluge M, Zhang RZ, Mayer U, Timpl R, Chu ML (Aug 1993). "Sequence of extracellular mouse protein BM-90/fibulin and its ...
"Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene". Nature. 353: 844- ... Subsequently, he was a co-inventor on the original patents that covered three mutations in the amyloid precursor protein (APP) ... "Amyloid precursor protein in alzheimer's disease", published 1998-08-18 Goate A, Chartier-Harlin MC, Mullan M, Brown J, ... "Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease". Nature. 349: 704- ...
"Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy- ... The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when ... complex with the γ-secretase activating protein facilitates the gamma cleavage of amyloid precursor protein into β-amyloid. The ... Zhang, H; Ma, Q; Zhang, YW; Xu, H (January 2012). "Proteolytic processing of Alzheimer's β-amyloid precursor protein". Journal ...
"Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein". ... beta-secretase site of the amyloid precursor protein". The Journal of Biological Chemistry. 283 (12): 7745-53. doi:10.1074/jbc. ... animal model expressing human amyloid precursor protein (APP) containing the wild-type beta-secretase site sequence found in ... Klein DM, Felsenstein KM, Brenneman DE (March 2009). "Cathepsins B and L differentially regulate amyloid precursor protein ...
Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. February 1995, ... Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein. Biochem. Soc. Trans ... Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and ... 1991年,學者提出類澱粉胜肽假說,認為β類澱粉胜肽(英语:Beta amyloid)(Aβ)在大腦堆積可能是
... localization in human cerebral cortex and generation of amyloidogenic fragments from the beta-amyloid precursor protein". ... Cathepsin G is a protein that in humans is encoded by the CTSG gene. It is one of the three serine proteases of the ... Gabay JE, Scott RW, Campanelli D, Griffith J, Wilde C, Marra MN, Seeger M, Nathan CF (July 1989). "Antibiotic proteins of human ... Cathepsin G is a 255-amino-acid-residue protein including an 18-residue signal peptide, a two-residue activation peptide at the ...
2002). "The gamma-secretase-generated intracellular domain of beta-amyloid precursor protein binds Numb and inhibits Notch ... Numb-like protein is a protein that in humans is encoded by the NUMBL gene. NUMBL has been shown to interact with MAP3K7IP2. ... 2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. ... a novel protein-protein interaction module". Genes Dev. 11 (17): 2239-49. doi:10.1101/gad.11.17.2239. PMC 275390 . PMID 9303539 ...
"Transgenic tomatoes expressing human beta-amyloid for use as a vaccine against Alzheimer's disease". Biotechnology letters. 30 ... Kurstaki Insect Control Protein". Nature Biotechnology. 7 (12): 1265-1269. doi:10.1038/nbt1289-1265.. ... the precursor to ethylene. DNAP's tomato, called Endless Summer, inserted a truncated version of the ACC synthase gene into the ... "Fruit Cell Wall Proteins Help Fungus Turn Tomatoes From Ripe To Rotten". Science Daily. Jan 31, 2008. Retrieved 29 August 2010. ...
P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving ... P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving ... P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving ... Based on this hypothesis, beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors are an attractive ...
Aβ is cleaved from the β-amyloid precursor protein (AβPP) by β-secretase and γ-secretase. Heterogeneity of the C-terminal is ... Beta amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimers disease. An ... seven amyloid proteins have been reported in CAA including amyloid β-protein (Aβ), cystatin C (ACys), prion protein (APrP), ... Some mutations in the amyloid β-protein precursor (AβPP) and presenilin genes are associated with severe CAA [see review5]. ...
beta/A4 amyloid is derived from the amyloid precursor protein (APP), an integral membrane protein that exists as three major ... Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. G L Caporaso, S E Gandy, J D ... Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. G L Caporaso, S E Gandy, J D ... Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. G L Caporaso, S E Gandy, J D ...
APBB2 amyloid beta precursor protein binding family B member 2 [Homo sapiens] APBB2 amyloid beta precursor protein binding ... The protein encoded by this gene interacts with the cytoplasmic domains of amyloid beta (A4) precursor protein and amyloid beta ... General protein information Go to the top of the page Help Preferred Names. amyloid-beta A4 precursor protein-binding family B ... mRNA and Protein(s) * NM_001166050.1 → NP_001159522.1 amyloid-beta A4 precursor protein-binding family B member 2 isoform b ...
Beta-amyloid precursor protein staining of nonaccidental central nervous system injury in pediatric autopsies.. Reichard RR1, ... Immunohistochemical staining for beta-amyloid precursor protein (betaAPP) is a well-established marker of traumatic axonal ...
The beta-amyloid precursor protein (betaAPP) is a transmembrane protein that is exclusively phosphorylated on serine residues ... Ectodomain phosphorylation of beta-amyloid precursor protein at two distinct cellular locations.. Walter J., Capell A., Hung A. ... APPssw-beta). This antibody previously established the cellular location of the beta-secretase cleavage of Swedish betaAPP as a ... European Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. UniProt is an ELIXIR core ...
AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary ... The amyloid plaques are composed of amyloid beta-peptide (A beta), a 40-42-amino-acid fragment of the beta-amyloid precursor ... Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein Nature. 1995 Feb 9;373( ... Amyloid beta-Peptides / metabolism* * Amyloid beta-Protein Precursor / genetics * Amyloid beta-Protein Precursor / metabolism ...
apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor. I Daigle and C Li ... apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor ... apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor ... apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor ...
Amyloid beta protein toxicity mediated by the formation of amyloid-beta protein precursor complexes. Lu, D.C., Shaked, G.M., ... The amyloid beta-protein precursor (APP) is proteolytically cleaved to generate the amyloid beta-protein (Abeta), the principal ... In vivo, the levels of soluble amyloid beta protein correlated with caspase-cleaved fragments of the amyloid precursor protein ... Caspase cleavage of the amyloid precursor protein modulates amyloid beta-protein toxicity. Lu, D.C., Soriano, S., Bredesen, D.E ...
A beta) is an invariant feature of Alzheimers disease which precedes symptoms of dementia by years or decades. The only ... Progressive cerebral deposition of the 39-43-amino-acid amyloid beta-protein ( ... Mutation of the beta-amyloid precursor protein in familial Alzheimers disease increases beta-protein production Nature. 1992 ... disease which have been identified so far are missense mutations in the gene encoding the beta-amyloid precursor protein (beta- ...
Compare amyloid beta precursor protein binding family A member 2 ELISA Kits from leading suppliers on Biocompare. View ... amyloid beta precursor protein binding family A member 2 ELISA Kits. Clear ... amyloid beta precursor protein binding family A member 2 ELISA Kits. The ELISA (enzyme-linked immunosorbent assay) is a well- ... Bovine Amyloid beta A4 precursor protein-binding family A member 2 (APBA2) ELISA Kit ...
Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma ... have been identified based upon the region of amyloid protein precursor they cleave. ... Amyloid Precursor Protein Secretases (beta-Secretase). Subscribe to New Research on Amyloid Precursor Protein Secretases ... beta-Secretase; alpha-Secretase; gamma-Secretase; Secretase; APP Secretase; Amyloid Precursor Protein Secretase; Secretases; ...
Amyloid beta (A4) precursor protein degradation products. Debate and discussion of any biological questions not pertaining to a ... Amyloid beta (A4) precursor protein degradation products of the pathogenic role of Alzheimers disease research progress. APP ... Cutting followed by the β and γ-secretase enzyme, resulting in extracellular s APP beta, A beta (A beta 40 and A beta 42) ... resulting in excess of A beta 40 and A beta 42, the formation of A beta deposition as the core of senile plaques and disease. ...
Adapter protein that forms a transcriptionally active complex with the gamma-secretase-derived amyloid precursor protein (APP) ... Protein. Similar proteins. Species. Score. Length. Source. P46933. Amyloid-beta A4 precursor protein-binding family B member 1 ... "Regulation of beta-amyloid secretion by FE65, an amyloid protein precursor-binding protein.". Sabo S.L., Lanier L.M., Ikin A.F. ... "Regulation of beta-amyloid secretion by FE65, an amyloid protein precursor-binding protein.". Sabo S.L., Lanier L.M., Ikin A.F. ...
... amyloid beta precursor protein binding family A member 2), Authors: Dessen P. Published in: Atlas Genet Cytogenet Oncol ... amyloid beta (A4) precursor protein-binding, family A, member 2 (X11-like). ... amyloid-beta binding in utero embryonic development protein binding cytoplasm plasma membrane chemical synaptic transmission ... amyloid-beta binding in utero embryonic development protein binding cytoplasm plasma membrane chemical synaptic transmission ...
8-Tetrahydropyran-2-yl chromans: highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors. * ... 8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors.. ... Beta-secretase 1. A. 406. Homo sapiens. Mutation(s): 0 Gene Names: BACE1, BACE, KIAA1149. EC: 3.4.23.46. ...
We perform a single molecule level study of the RERMS sequence of amyloid $\beta $/A4 precursor protein fragment on a clean Ag( ... Abstract: D10.00003 : Single Molecule Manipulation and Self-Assembly of Amyloid $\beta $/A4 Precursor Protein on Ag(111)*. 3:18 ... Moreover, we are able to form a well ordered two-dimensional layer of the protein fragment by increasing the deposition time. A ... The mechanical stability of individual protein fragments are checked by laterally manipulating them with the STM tip. ...
... beta] Precursor Protein/Presenilin 2 Mouse Model of Alzheimers Disease.(Research Article) by International Journal of ... Early Contextual Fear Memory Deficits in a Double-Transgenic Amyloid-[ ... MLA style: "Early Contextual Fear Memory Deficits in a Double-Transgenic Amyloid-[beta] Precursor Protein/Presenilin 2 Mouse ... APA style: Early Contextual Fear Memory Deficits in a Double-Transgenic Amyloid-[beta] Precursor Protein/Presenilin 2 Mouse ...
A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. Young- ... AAV Data Hub Beta Open collection of AAV data generously shared by scientists ...
cerebrospinal fluid, beta-amyloid, apolipoprotein E, Alzheimers disease, amyloid precursor protein, ELISA, mild cognitive ... Measurement of alpha- and beta-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients. ... is redundant senile plaques mainly composed of beta-amyloid (Abeta) aggregates. Alternative cleavage of the amyloid precursor ... is redundant senile plaques mainly composed of beta-amyloid (Abeta) aggregates. Alternative cleavage of the amyloid precursor ...
Synthetic Human Amyloid beta (A4) Precursor Protein (aa 737-751)(CT) Blocking Peptide ... Synthetic Human Amyloid beta (A4) Precursor Protein (aa 737-751)(CT) Blocking Peptide. ...
Conclusions: : Both amyloid-beta (AB) and amyloid precursor protein (APP) appear to be present in AD and normal optic nerves ... Immunohistochemical Identification of Amyloid-Beta and Amyloid Precursor Protein in Alzheimers Disease Optic Nerve and Retina ... Immunohistochemical Identification of Amyloid-Beta and Amyloid Precursor Protein in Alzheimers Disease Optic Nerve and Retina ... D. Aggarwal, F. N. Ross-Cisneros, A. A. Sadun; Immunohistochemical Identification of Amyloid-Beta and Amyloid Precursor Protein ...
Synthetic Human Amyloid beta (A4) Precursor Protein A beta NT (aa 653-662) Peptide ... Synthetic Human Amyloid beta (A4) Precursor Protein A beta NT (aa 653-662) Peptide. ...
Retinal Amyloid Precursor Protein (APP) processing and amyloid-beta (Aβ) transport in an Alzheimers disease (AD) mouse model ... Retinal Amyloid Precursor Protein (APP) processing and amyloid-beta (Aβ) transport in an Alzheimers disease (AD) mouse model ... Retinal Amyloid Precursor Protein (APP) processing and amyloid-beta (Aβ) transport in an Alzheimers disease (AD) mouse model. ... Results : AD mice retinas exhibited enhanced APP production with increased amyloid processing and Aβ accumulation vs. wt mice. ...
... precursor protein (APP), transcript variant 5 as transfection-ready DNA - 10 µg - OriGene - cdna clones ... Myc-DDK-tagged ORF clone of Homo sapiens amyloid beta (A4) ... Myc-DDK-tagged ORF clone of Homo sapiens amyloid beta (A4) ... home , products , origene , myc-ddk-tagged orf clone of homo sapiens amyloid beta (a4) precursor protein (app), transcript ... Myc-DDK-tagged ORF clone of Homo sapiens amyloid beta (A4) precursor protein (APP), transcript variant 5 as transfection-ready ...
  • Amyloid beta (Abeta) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from AD patients, genetic analysis of mutations that cause early onset forms of AD, and preclinical studies. (geoscience.net)
  • These studies showed that all three BACE1 inhibitors decreased brain Abeta1-40 in P-gp KO mice, demonstrating that P-gp is a major limitation for development of BACE1 inhibitors to test the amyloid hypothesis. (geoscience.net)
  • Formalin-fixed, paraffin-embedded 5µm sections of 30 optic nerves and retinas from 15 donors previously diagnosed with AD and 30 age-matched control optic nerves and retinas from 15 individuals with no AD, other neurodegenerative diseases, diabetes mellitus, or sepsis were stained with antibodies reactive against amyloid-beta (AB) and amyloid precursor protein (APP). (arvojournals.org)
  • By visualizing the distribution of beta PP monoclonal antibodies added to intact cultures, beta PP was shown to be internalized from distal axons or terminals and retrogradely transported back to perikarya in organelles which colocalized with fluid-phase endocytic markers. (rupress.org)
  • Search, Find and Buy Antibodies, ELISA Kits and Proteins. (antibodies-online.com)
  • We found that neither the level of CSF-alpha-sAPP nor CSF-beta-sAPP differed between sporadic AD patients and healthy controls. (lu.se)
  • However, the level of CSF-beta-sAPP was significantly increased in patients with mild cognitive impairment compared to controls. (lu.se)
  • Here we report that cultured cells which express a beta-APP complementary DNA bearing a double mutation (Lys to Asn at residue 595 plus Met to Leu at position 596) found in a Swedish FAD family produce approximately 6-8-fold more A beta than cells expressing normal beta-APP. (nih.gov)
  • PS2M1 mice express human PS2 proteins containing the N141I mutation on a C57BL/6JJcl background (purchased from Immuno-Biological Laboratories Co, Ltd., Fujioka, Japan) [22, (thefreelibrary.com)
  • The most common APP mutation changes one of the protein building blocks (amino acids) in the amyloid precursor protein. (medlineplus.gov)
  • This mutation replaces the amino acid valine with the amino acid isoleucine at protein position 717 (written as Val717Ile or V717I). (medlineplus.gov)
  • [ 72 ] Finally, recent research on patients with mild closed head injuries has found that although increased glial fibrillary acid protein (GFAP) levels correlated with abnormal neuroimaging, both GFAP and S100B failed to significantly correlate with clinical outcomes. (medscape.com)
  • Inhibition studies and the finding that cell surface APP can serve as a direct precursor of βA4 suggest that the endosomal/lysosomal compartment is involved in the proteolysis of APP into βA4. (jneurosci.org)
  • Addressing both, we applied intravitreally a beta secretase (BACE) inhibitor in an AD mouse model (SwAPP/Psen1d9), and investigated possible clearance pathways for Aβ. (arvojournals.org)
  • Among its related pathways are DNA Double Strand Break Response and Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins. . (genecards.org)
  • Among its related pathways are Protein-protein interactions at synapses and Transmission across Chemical Synapses . (genecards.org)
  • The major molecules involved in these pathways include: glial cells (specifically astrocytes and microglia), beta-amyloid, and pro-inflammatory compounds. (wikipedia.org)
  • It is a key structural component of a great number of proteins, and a co-factor of more than 300 enzymes that regulate a variety of cellular processes and cellular signaling pathways essential for both brain and systemic physiology ( Takeda, 2000 ). (frontiersin.org)
  • May interact with cellular G-protein signaling pathways. (abcam.com)
  • We illustrate its use in exploring protein aggregation in neurodegenerative disease and in the expansion of pathways associated to colon cancer. (biomedcentral.com)
  • In these studies we utilize we use biochemical, molecular, and cell biological methods to characterize the role of these proteins in signal transduction pathways in striatal neurons. (yale.edu)
  • Secreted forms of APP found in blood plasma and cerebrospinal fluid arise by proteolytic cleavage of APP within the beta/A4 amyloid domain, precluding the possibility of amyloidogenesis for that population of molecules. (pnas.org)
  • AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. (nih.gov)
  • Increased APP phosphorylation and altered expression levels of the brain enriched Fe65 protein have been observed in the brains of AD patients. (diva-portal.org)
  • The 50 % reduction in phenylalanine and tyrosine in HIP brains is significant given their role in supporting brain chemistry as a precursor for catecholamines (dopamine, norepinephrine, epinephrine), which may contribute to the increased morbidity and mortality in diabetics at a multi-system level beyond the effects on glucose metabolism. (springer.com)
  • Here we show the presence of misfolded prion protein (PrP(Sc)-like) in extracts of various sections of the brains of two SIDS victims. (biomedsearch.com)
  • These mutations are located within or immediately flanking the A beta region of beta-APP, but the mechanism by which they cause the pathological phenotype of early and accelerated A beta deposition is unknown. (nih.gov)
  • Links are provided to the PDB's Molecule of the Month , where the structural features of the proteins are explored in detail, and, when applicable, to the EXPASY Protein Spotlight to gain another view of the featured proteins. (ebi.ac.uk)
  • Effects of ICT on the mRNA expression of APP were assessed by quantitative polymerase chain reaction, and protein expression was measured by western blotting and immunofluorescence. (peerj.com)
  • A beta generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. (uni-muenchen.de)
  • Moreover, eASN upregulated expression of Sirt3 and Sirt5 , but downregulated of Sirt1 , which plays an important role in cell metabolism including Aβ precursor protein (APP) processing. (springer.com)
  • Moreover, higher expression of pro-apoptotic protein Bax and enhancement of apoptotic cells' death were observed. (springer.com)
  • Transcription is the first step in protein expression and the major point of regulation of the components that determine the characteristics, fate and functions of cells. (mdpi.com)
  • Though translation of the mRNA message, as well as modification and correct folding of the polypeptide chains are essential for the protein composition of a cell, expression of all the components begins by transcription from DNA. (mdpi.com)
  • Selective regulation of protein translation. (yale.edu)
  • Glutathione-Responsive Selenosulfide Prodrugs as a Platform Strategy for Potent and Selective Mechanism-Based Inhibition of Protein Tyrosine Phosphatases. (yale.edu)