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 ...
Anti-β-Amyloid Precursor-Like Protein 1, C-Terminal (643-653) Rabbit pAb - Find MSDS or SDS, a COA, data sheets and more information.
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 ...
TY - JOUR. T1 - The Rat Central Nervous System Expresses Alzheimers Amyloid Precursor Protein APP695, but Not APP677 (L‐APP Form). AU - Ohgami, Tetsuya. AU - Kitamoto, Tetsuyuki. AU - Tateishi, Jun. PY - 1993/10. Y1 - 1993/10. N2 - Abstract: A novel splicing form of βA4 amyloid precursor protein (APP) lacking exon 15, corresponding to 18 residues, was first reported in leukocytes and then in ubiquitous organs. To determine which APP molecules (APP695, APP751, or APP770) either with (N‐APP) or without (L‐APP; leukocytederived APP) exon 15 were expressed in various organs, we investigated the alternative splicing at exon 15 in the rat brain, kidney, heart, and testis by a PCR analysis of reverse‐transcribed RNA and Southern blot analysis. Regarding APP695 without exons 7 and 8, L‐APP was either seldom or never expressed in the brain, whereas both N‐ and L‐APP were expressed in other organs. On the other hand, regarding APP751/770 containing exon 7, which codes for the Kunitz‐type ...
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 ...
TY - JOUR. T1 - Gene expression profiles of transcripts in amyloid precursor protein transgenic mice. T2 - Up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimers disease. AU - Reddy, P. Hemachandra. AU - McWeeney, Shannon. AU - Park, Byung S.. AU - Manczak, Maria. AU - Gutala, Ramana V.. AU - Partovi, Dara. AU - Jung, Youngsin. AU - Yau, Vincent. AU - Searles, Robert. AU - Mori, Motomi. AU - Quinn, Joseph. N1 - Funding Information: The authors thank Sandra Oster, Neurological Sciences Institute, Oregon Health and Science University, for critical reading of the manuscript. This research was supported in part by the Alzheimers Association of Oregon, the Medical Research Foundation of Oregon, the American Federation for Aging Research, a pilot grant from the Alzheimers Disease Center of Oregon, P30 AG08017, and AG22643 (to P.H.R.) and Department of Veterans Affairs Advanced Research Career Development Award and NIH-AT0006 (to J.Q.).. PY - ...
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 ...
APBA2 (amyloid beta precursor protein binding family A member 2), 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
Accumulation of the amyloid A beta peptide, which is derived from a larger precursor protein (APP), and the formation of plaques, are major events believed to be involved in the etiology of Alzheimers disease. Abnormal regulation of the metabolism of APP may contribute to the deposition of plaques. APP is an integral membrane protein containing several putative phosphorylation sites within its cytoplasmic domain. We report here that APP is phosphorylated at Thr668 by p34(cdc2) protein kinase (cdc2 kinase) in vitro, and in a cell cycle-dependent manner in vivo. At the G(2)/M phase of the cell cycle, when APP phosphorylation is maximal, the levels of mature APP (mAPP) and immature APP (imAPP) do not change significantly. However, imAPP is altered qualitatively. Furthermore, the level of the secreted extracellular N-terminal domain (APP(S)) is decreased and that of the truncated intracellular C-terminal fragment (APP(COOH)) is increased. These findings suggest the possibility that ...
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 ...
Weight loss is a prominent early feature of Alzheimers disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons ...
Processing from the amyloid proteins precursor (APP) from the and secretases potential clients to the creation of two little peptides, amyloid as well as the APP intracellular site (Help, or called elsewhere AICD). in conjunction with Fe65 by 1st displaying that although Fe65 enters the nucleus in the lack of full-length APP, JIP-1 will not. Additionally, JIP-1-induced activation can be Suggestion60 3rd party, whereas a complicated with Help, Fe65, and Suggestion60 can be shaped for Fe65-induced activation. Finally, and most interestingly probably, we display that even though the APP family APLP1 and APLP2 (for amyloid precursor-like protein) can cause activation in combination Rabbit polyclonal to AACS with Fe65, APLP1 and APLP2 show little or no activation in combination with JIP-1. This activity for the AID fragment may help explain the unique functions of APP relative to its other family members, and changes in gene expression found in Alzheimers disease. The importance of amyloid protein ...
In 31 symptomatic and 5 asymptomatic carriers of the amyloid precursor protein (APP) gene codon 693 mutation, 10 family members without mutation, and 5 carriers of the APP gene codon 692 mutation (3 with early-onset Alzheimer dementia, 2 with cerebral hemorrhage), a high frequency of the apolipoprotein E epsilon 4 allele was found. Age at onset, age at death, occurrence of dementia, and number of strokes did not differ between APP gene mutation carriers with or without epsilon 4 allele, showing that the clinical expression of these APP mutations is not influenced by the apolipoprotein E gene.
Growth factors are substances that are capable of stimulating cellular proliferation, differentiation, as well as growth. Another probable hypothesis is that the membrane-bound APP may be involved in cell signaling, which is the complex communication system used by cells to govern basic cellular activities and actions. Molecules of APP that are not cleaved by α-secretase are capable of forming internalized endocytic compartments, which in turn are subsequently cleaved by β- and γ- secretases (6). γ- secretase carries out proteolytic modification further by processing the membrane-bound peptide into the amyloid beta (Aβ) peptide form (7). Generation of the Aβ peptide is borne solely from the cleavage of APP in which the amyloid precursor protein intracellular domain (AICD) is released and deposited in aggregated fibrils in senile plaques. Other APP protein family members do not form the Aβ peptide deposits on cleavage (6). It is important to restate that the physiological function of ...
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 ...
The selectivity of LAG3, neurexin 1β, and APLP1 and related transmembrane proteins for α-syn-biotin PFF versus α-syn-biotin monomers was determined via the ratio of Kd values (Fig. 1B). LAG3 exhibited the highest selectivity with a ratio of 38, followed by neurexin 1β with a ratio of 11 and APLP1 with a ratio of 7. The binding of α-syn-biotin PFF to LAG3 was specific because α-syn-biotin PFF does not bind to the CD4 receptor, which has 20% homology to LAG3 (Fig. 1B and fig. S4). In addition to α-syn-biotin PFF binding to neurexin 1β, it also binds to neurexin 3β and mildly binds to neurexin 1α and neurexin 2β (Fig. 1B). α-Syn-biotin PFF does not bind the amyloid precursor protein (APP) or the amyloid precursor-like protein 2 (APLP2), suggesting that the binding to APLP1 was specific (Fig. 1B). Because LAG3 exhibited the highest selectivity for α-syn-biotin PFF, it was advanced for further study. No LAG3 immunoreactive band was observed in HEK293FT and SH-SY5Y cells, which is ...
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 ...
Sequential proteolysis of the amyloid precursor protein (APP) and amyloid-beta petide (Abeta) release is an upstream event in Alzheimers disease (AD) pathogenesis. The function of APP in neuronal physiology is still, however, poorly understood. Along with its paralog APP-like Proteins 1 and 2 (APLP1-2), APP is involved in neurite formation and synaptic function by mechanisms that are not elucidated. APP is a single-pass transmembrane protein expressed at high levels in the brain that resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies on cell interaction processes and/or activation of intracellular pathways of signal transduction. Along this line, the APP intracellular domain (AICD) was reported to act as a transcriptional factor for targeted gene activation that mediates physiological APP functions. Here, we used an unbiased transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent embryonic cortex and upon ...
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 ...
Synonyms: Amyloid Beta A4 Protein, APPI, ABPP, Alzheimer Disease Amyloid Protein, Beta-amyloid Precursor Protein, Cerebral Vascular Amyloid Peptide, CVAP, PreA4, Protease Nexin-II, PN-II ...
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. N1 - Funding Information: This work was supported by Japan Society for the Promotion of Science (JSPS) Grant 17H06421 (to M. K.) and by CREST (to H. I., N. I., and T. T.). The authors declare that they have no conflicts of interest with the contents of this article. Publisher Copyright: © 2020 Seki et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.. 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. ...
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 ...
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TY - JOUR. T1 - Copper Depletion Down-regulates Expression of the Alzheimers Disease Amyloid-β Precursor Protein Gene. AU - Bellingham, Shayne A.. AU - Lahiri, Debomoy K.. AU - Maloney, Bryan. AU - La Fontaine, Sharon. AU - Multhaup, Gerd. AU - Camakaris, James. PY - 2004/5/7. Y1 - 2004/5/7. N2 - Alzheimers disease is characterized by the accumulation of amyloid-β peptide, which is cleaved from the amyloid-β precursor protein (APP). Reduction in levels of the potentially toxic amyloid-β has emerged as one of the most important therapeutic goals in Alzheimers disease. Key targets for this goal are factors that affect the regulation of the APP gene. Recent in vivo and in vitro studies have illustrated the importance of copper in Alzheimers disease neuropathogenesis and suggested a role for APP and amyloid-β in copper homeostasis. We hypothesized that metals and in particular copper might alter APP gene expression. To test the hypothesis, we utilized human fibroblasts overexpressing the ...
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.
It is well established that the human brain exhibits regional variability in its vulnerability to Alzheimers disease (AD) pathology. We set out to determine if this regional vulnerability is reflected in the expression pattern, or processing, of two key proteins involved in AD pathology, the β-amyloid precursor protein (APP) and tau, by immunoblotting. Our data demonstrate that APP processing and APP protein levels are not different between AD patients and healthy, age-matched subjects, but that levels of mature APP are greatly reduced in cerebellum compared to regions of the brain most vulnerable to AD, entorhinal cortex and hippocampus. In addition, protein levels of tau are significantly reduced in cerebellum compared to all other human brain regions examined. Unexpectedly, protein levels of glycogen synthase kinase 3 (GSK3), a major tau kinase, are at their lowest in hippocampus. The observations demonstrate that both mature APP as well as total APP and tau protein levels are greatly reduced in
Accumulation of A beta peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimers disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic A beta peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by beta-secretase and gamma-secretase inhibition, as well as gamma-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular A beta signaling to ...
New neurons incorporate into the granular cell layer of the dentate gyrus throughout life. Neurogenesis is modulated by behavior and plays a major role in hippocampal plasticity. Along with older mature neurons, new neurons structure the dentate gyrus and determine its function. Recent data suggest that the level of hippocampal neurogenesis is substantial in the human brain, suggesting that neurogenesis may have important implications for human cognition. In support of that, impaired neurogenesis compromises hippocampal function and plays a role in cognitive deficits in Alzheimers disease mouse models. We review current work suggesting that neuronal differentiation is defective in Alzheimers disease, leading to dysfunction of the dentate gyrus. Additionally, alterations in critical signals regulating neurogenesis, such as presenilin-1, Notch 1, soluble amyloid precursor protein, CREB, and β-catenin underlie dysfunctional neurogenesis in Alzheimers disease. Lastly, we discuss the detectability of
TY - JOUR. T1 - Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus. T2 - Revisited. AU - Lazarov, Orly. AU - Morfini, Gerardo A.. AU - Lee, Edward B.. AU - Farah, Mohamed H.. AU - Szodorai, Anita. AU - DeBoer, Scott R.. AU - Koliatsos, Vassilis E.. AU - Kins, Stefan. AU - Lee, Virginia M.Y.. AU - Wong, Philip C.. AU - Price, Donald L.. AU - Brady, Scott T.. AU - Sisodia, Sangram S.. N1 - Copyright: Copyright 2008 Elsevier B.V., All rights reserved.. PY - 2005/3/2. Y1 - 2005/3/2. N2 - The sequential enzymatic actions of β-APP cleaving enzyme 1 (BACE1), presenilins (PS), and other proteins of the γ-secretase complex liberate β-amyloid (Aβ) peptides from larger integral membrane proteins, termed β-amyloid precursor proteins (APPs). Relatively little is known about the normal function(s) of APP or the neuronal compartment(s) in which APP undergoes proteolytic processing. Recent studies have been interpreted as consistent with the idea that APP serves as a ...
This new book presents a summary of Alzheimers disease-related ischemic protein changes and gene expression as risk factors for the late-onset of sporadic Alzheimers disease, and their role in Alzheimers disease ischemic etiology. Ischemic brain changes were noted in the staining of different parts of an amyloid protein precursor, presenilin 1 and 2, tau protein, alfa-synuclein, and apolipoproteins A1, E and J.. Current advances in understanding the ischemic etiology of Alzheimers disease has revealed dysregulation of Alzheimers disease-associated genes including presenilin 1 and 2, β-secretase, amyloid protein precursor, apoptosis, autophagy, mitophagy, and tau protein. This book presents the relationship between these genes, dysregulated by cerebral ischemia, and the cellular and tissue neuropathology characteristic of Alzheimers disease. This book draws attention to the latest research confirming the theory that Alzheimers disease-related proteins and genes play an important role in ...
Title: Neurodegeneration and Neurogenesis: Focus on Alzheimers Disease. VOLUME: 3 ISSUE: 1. Author(s):David A. Greenberg and Kunlin Jin. Affiliation:Buck Institute for Age Research,8001 Redwood Boulevard, Novato, CA 94945, USA.. Keywords:Neurodegeneration, neurogenesis, neuronal precursor cells, stem cells, hippocampus, dentate gyrus. Abstract: Neurogenesis, or the production of new neurons from neuronal precursor cells, is a normal phenomenon in the adult brain, and is accentuated by brain injury. Forms of injury associated with increased neurogenesis include both acute (e.g., stroke) and chronic neurodegenerations. Studies on human postmortem material and transgenic mice overexpressing amyloid precursor protein mutations found in familial Alzheimers disease (AD) suggest that AD is associated with enhanced neurogenesis. However, the mechanism responsible for this effect is unknown, as is what influence it may have on the clinical course of murine or human AD. If AD leads to the production of ...
The protein encoded by this gene is a member of the Fe65 protein family. It is an adaptor protein localized in the nucleus. It interacts with the Alzheimers disease amyloid precursor protein (APP), transcription factor CP2/LSF/LBP1 and the low-density lipoprotein receptor-related protein. APP functions as a cytosolic anchoring site that can prevent the gene products nuclear translocation. This encoded protein could play an important role in the pathogenesis of Alzheimers disease. It is thought to regulate transcription. Also it is observed to block cell cycle progression by downregulating thymidylate synthase expression. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene ...
NEDD8-activating enzyme E1 catalytic subunit is a protein that in humans is encoded by the UBA3 gene.[5][6] The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E1 ubiquitin-activating enzyme family. The encoded enzyme associates with AppBp1, an amyloid beta precursor protein binding protein, to form a heterodimer, and then the enzyme complex activates NEDD8, a ubiquitin-like protein, which regulates cell division, signaling and embryogenesis. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[6] This enzyme contains an E2 binding domain, which resembles ubiquitin, and recruits the catalytic core of the E2 enzyme UBE2M (Ubc12) in a similar ...
0037]The term amyloid-β (or Aβ) as used herein has the standard meaning understood in the art. The full length beta amyloid precursor protein (APP) occurs in nature in several variants, up to 770 amino acids in length, with other characterized species including variants 695, 639, 574, 547, 484, 352, 327 and 305 amino acids in length. Amyloid-β polypeptides may be of various lengths, including 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, ...
The crystal structures of the inhibitor domain of Alzheimers amyloid beta-protein precursor (APPI) complexed to bovine chymotrypsin (C-APPI) and trypsin (T-APPI) and basic pancreatic trypsin inhibitor (BPTI) bound to chymotrypsin (C-BPTI) have been solved and analyzed at 2.1 A, 1.8 A, and 2.6 A resolution, respectively. APPI and BPTI belong to the Kunitz family of inhibitors, which is characterized by a distinctive tertiary fold with three conserved disulfide bonds. At the specificity-determining site of these inhibitors (P1), residue 15(I)4 is an arginine in APPI and a lysine in BPTI, residue types that are counter to the chymotryptic hydrophobic specificity. In the chymotrypsin complexes, the Arg and Lys P1 side chains of the inhibitors adopt conformations that bend away from the bottom of the binding pocket to interact productively with elements of the binding pocket other than those observed for specificity-matched P1 side chains. The stereochemistry of the nucleophilic hydroxyl of Ser 195 ...
1CA0: Crystal structures of bovine chymotrypsin and trypsin complexed to the inhibitor domain of Alzheimers amyloid beta-protein precursor (APPI) and basic pancreatic trypsin inhibitor (BPTI): engineering of inhibitors with altered specificities.
The Amyloid Precursor Protein (APP) is a transmembrane protein whose cleavage results in toxic Aß fragment identified as the major constituent in the amyloid plaques of Alzheimers Disease. Recent evidence has shown that fragments of APP including its intracellular domain are secreted into the extracellular space, possibly via the formation and release of extracellular vesicles called exosomes, which are derived from endosomes. in the Drosophila model, we have manipulated specific components of the membrane trafficking machinery predicted to be involved in APP traffic, and measured their effects on in vivo APPeGFP exosome secretion using fluorescence quantification. We targeted the Vps35, Snx1, and Snx3 components of the endosomal sorting complex called Retromer (which is implicated in Alzheimers Disease), and the GTPase Rab11 which has been implicated in exocytosis. Our results indicate that Rab11 and the Snx1 are required for exosome release while Snx3 and Vps35, perhaps working together ...
The Alzheimers disease (AD)-associated presenilin (PS) proteins are required for the γ-secretase cleavages of the β-amyloid precursor protein and the site 3 (S3) protease cleavage of Notch. These intramembrane cleavages release amyloid-β peptide (Aβ), including the pathogenic 42-aa variant (Aβ(42)), as well as the β-amyloid precursor protein and the Notch intracellular domains (AICD, NICD). Whereas Aβ is generated by endoproteolysis in the middle of the transmembrane domain, AICD and NICD are generated by cleavages at analogous positions close to the cytoplasmic border of the transmembrane domain. Numerous mutations causing familial AD (FAD) that all cause increased production of Aβ(42) have been found in the PS1 gene. Here we have investigated the previously uncharacterized, very aggressive FAD mutation L166P that causes onset of AD in adolescence. Strikingly, the PS1 L166P mutation not only induces an exceptionally high increase of Aβ(42) production but also impairs NICD production ...
The Italian type and Arctic type are also caused by changes to glutamic acid at position In the Italian type, glutamic acid is replaced with the amino acid lysine written as Glu22Lys or E22K and in the Arctic type, glutamic acid is replaced with the amino acid glycine written as Glu22Gly or E22G.. More than 50 different mutations in the APP gene can cause early-onset Alzheimer disease, which begins before age Controlling neural stem cell division within the adult subventricular zone: The amyloid hypothesis of Alzheimers disease: These mutations change single amino acids in the amyloid precursor protein. When these protein fragments are released from the cell, they can accumulate in the brain and form clumps called amyloid plaques. ...
In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease.[54][55] Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of AD by 40 years of age.[56][57] Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.[58] Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimers-like brain pathology with spatial learning deficits.[59]. An experimental vaccine was found to clear the amyloid plaques in early ...
A cross-sectional and a longitudinal design were employed to address whether PDAPP mice exhibit any plaque-related learning deficit. Firstly, the cross-sectional study indicated that PDAPP mice simultaneously displayed an early (plaque-independent) and age-related learning impairment. Further analysis showed that the age-related learning deficit was highly correlated with plaque burden in the hippocampus of aged PDAPP mice, suggesting that amyloid plaques play a very important role in memory loss of AD. Second, the longitudinal study showed that the same PDAPP mice exhibited significant age-related learning deficits in trials to criterion and learning capacity tasks when they aged. Interestingly, cued navigation and object recognition in both cross-sectional and longitudinal studies were unaffected, indicating normal sensorimotor function and recognition memory of PDAPP mice. The longitudinal study further showed that the age-related learning impairment was significantly correlated with ...
TY - JOUR. T1 - APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38. AU - Moro, Maria Luisa. AU - Giaccone, Giorgio. AU - Lombardi, Raffaella. AU - Indaco, Antonio. AU - Uggetti, Andrea. AU - Morbin, Michela. AU - Saccucci, Stefania. AU - Di Fede, Giuseppe. AU - Catania, Marcella. AU - Walsh, Dominic M.. AU - Demarchi, Andrea. AU - Rozemuller, Annemieke. AU - Bogdanovic, Nenad. AU - Bugiani, Orso. AU - Ghetti, Bernardino. AU - Tagliavini, Fabrizio. PY - 2012/12. Y1 - 2012/12. N2 - Aβ is the main component of amyloid deposits in Alzheimer disease (AD) and its aggregation into oligomers, protofibrils and fibrils is considered a seminal event in the pathogenesis of AD. Aβ with C-terminus at residue 42 is the most abundant species in parenchymal deposits, whereas Aβ with C-terminus at residue 40 predominates in the amyloid of the walls of large vessels. Aβ peptides with other C-termini have not yet been thoroughly investigated. We analysed Aβ38 in ...
Concentrated in the synapse of neurons is an amyloid precursor protein (APP) that extends across the plasma membrane. A portion of this protein contains an Aβ peptide sequence. This region comprises part of the DNA segment spanning APP that codes for proteins.[10]. In the formation of senile plaques, Aβ is cleaved from the amyloid precursor protein. Although three enzymes can process APP, only β-(beta) and γ-(gamma) secretase are directly involved in the formation of senile plaques. β-secretase (BACE) is a protease enzyme that cleaves proteins and peptides. This protease cleaves APP to further expose the carboxyl terminal fragments of Aβ. After the bulk of APP is released by this process, γ-secretase cleaves the remaining carboxyl fragments on the transmembrane domain. The sequential actions of γ-secretase following BACE activity results in Aβ protein fragments (amyloid beta) that are released into the extracellular space.[10] Eventually, the accumulation of amyloid beta outside of ...
Alzheimers disease (AD) is the most common age-related dementia, with the number of affected individuals expected to exceed 100 million worldwide by 2050. In Australia, Alzheimers disease is the third leading cause of death behind heart disease and cancer. Despite the significance of this disease there are currently no disease modifying drugs to treat Alzheimers disease.. One of the pathological hallmarks of Alzheimers disease is the cerebral deposition of plaques composed of Amyloid-beta (Aß) peptide. Aß is produced by sequential proteolytic cleavage of the ubiquitously expressed integral-membrane protein, amyloid ß-protein precursor. The Aß released typically ranges from 38 to 43 amino acids in length due to imprecise cleavage. Peptides Aß1-40 and Aß1-42 are two of the most common forms and have received the majority of research attention. Clearance of Aß is slowed in cerebrospinal fluid from Alzheimers disease patients, which likely contributes to its pathological deposition. The ...
Accumulating evidence suggests that neurons prone to degeneration in Alzheimers Disease (AD) exhibit evidence of re-entry into an aberrant mitotic cell cycle. Our laboratory recently demonstrated that, in a genomic amyloid precursor protein (APP) mouse model of AD (R1.40), neuronal cell cycle events (CCEs) occur in the absence of beta-amyloid (Aβ) deposition and are still dependent upon the amyloidogenic processing of the amyloid precursor protein (APP). These data suggested that soluble Aβ species might play a direct role in the induction of neuronal CCEs. Here, we show that exposure of non-transgenic primary cortical neurons to Aβ oligomers, but not monomers or fibrils, results in the retraction of neuronal processes, and induction of CCEs in a concentration dependent manner. Retraction of neuronal processes correlated with the induction of CCEs and the Aβ monomer or Aβ fibrils showed only minimal effects. In addition, we provide evidence that induction of neuronal CCEs are autonomous to primary
Antibodies , OptimAb Antibodies , OptimAbᵀᴹ Beta-Amyloid 17-24 , Monoclonal Antibody, purified; Beta-Amyloid forms are deposited in the CNS of patients with Alzheimer s disease and Down s syndrome. Biochemical analysis of the amyloid peptides isolated from Alzheimer s disease brain indicates that Beta-Amyloid (1-42) is the principal species associated with senile plaque amyloids, while Beta-Amyloid (1-40) is more abundant in cerebrovascular amyloid deposits. Both result from the cleavage of Amyloid Precursor Protein (APP) by secretases. The mAb 4G8 reacts to the abnormally processed isoforms, as well as precursor forms.; Host:MouseClone: 4G8Isotype: IgG2bReactivity: Human, MouseImmunogen: This antibody is reactive to residues 17-24 of Beta-Amyloid. The epitope lies within amino acids 18-22 of Beta-Amyloid (VFFAE)Concentration:1 mg/mLFormulation:PBS (no preservatives); The Ab was purified on Protein GApplications:The Ab is effective in immunoblotting (WB),
Current approved drugs for Alzheimers disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPPSL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD. Three-month-old Thy-1 AβPPSL mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP
Minocycline is a second-generation tetracycline that effectively crosses the blood-brain barrier. It has remarkable neuroprotective qualities in models of cerebral ischaemia, traumatic brain injury, Huntingtons and Parkinsons diseases. However, there is no evidence about neuroprotective effects of minocycline on AD. Alzheimers disease (AD) is a neurodegenerative disorder characterized neuropathologically by the presence of neuritic plaques containing amyloid fibrils and neurofibrillary tangles whose main component is paired helical filament composed of hyperphosphorylated tau. There are numerous lines of evidence that some of the neurotoxicity associated with AD is due to proteolytic fragments of the amyloid precursor protein (APP). In this study, it was found out that minocycline reduces neurotoxicity induced by various C-terminal fragments of APP through inhibition of cytochrome c release and caspase-12 activation.
Alzheimers disease (AD) is a progressive neurodegenerative disorder of the central nervous system. Two pathological hallmarks in the brain of AD patients are neurofibrillary tangles and senile plaques. The plaques consist mainly of beta-amyloid (Abeta) peptides that are produced from the amyloid precursor protein (APP), by sequential cleavage by beta- and gamma-secretase. Most previous studies have been focused on the C-terminal fragments of APP, where the Abeta sequence is localized. The purpose of this study was to search for N-terminal fragments of APP in cerebrospinal fluid (CSF) using mass spectrometry (MS). By using immunoprecipitation (IP) combined with matrix-assisted laser desorption/ionization time-of-flight MS as well as nanoflow liquid chromatography coupled to high resolution tandem MS we were able to detect and identify six novel N-terminal APP fragments [APP((18-119)), APP((18-121)), APP((18-122)), APP((18-123)), APP((18-124)) and APP((18-126))], having molecular masses of ...
Beta-amyloid production results from cleavage in the extracellular domain of APP by the beta-secretase (BACE1) , which results in the production of the APP C-terminal fragment C99. This fragment is further cleaved by the gamma-secretase at residues 40-42 to produce beta-amyloid 40 and 42 peptides. Beta-amyloid aggregation and neuritic plaque formation are pathologic hallmarks of Alzheimer disease. This peptide corresponds to the human beta-amyloid 1-40 peptide ...
In different parts of the of cell including the outermost part of the cell membrane, chemicals called enzymes snip the APP into small pieces. These enzymes that do the snipping are alpha-secretase, beta-secretase, and gamma-secretase. Depending on which enzyme is doing the snipping and what parts of the APP are snipped, two different things can happen. One that is helpful and one that causes the formation of beta-amyloid plaques. The plaques are formed when beta-secretase snips the APP molecule at one end of the beta-amyloid peptide, releasing sAPPβ from the cell. Gamma-secretase then cuts the pieces of APP that is left and, still sticking out of the neurons membrane, at the other end of the beta-amyloid peptide. After this snipping the beta-amyloid peptide is released into the space outside the neuron and begins to stick to other beta-amyloid peptides. These pieces stick together to form oligomers. Different oligomers of various sizes are now floating around in the spaces between the neurons, ...
Because soluble (or secreted) amyloid precursor protein-β (sAPPβ) and -α (sAPPα) possibly reflect pathological features of Alzheimers disease (AD), they are potential biomarker candidates for dementia disorders, including AD and mild cognitive impairment (MCI) due to AD (MCI-AD). However, controversial results have been reported regarding their alterations in the cerebrospinal fluid (CSF) of AD and MCI-AD patients. In this study, we re-assessed the utility of sAPPα and sAPPβ in CSF as diagnostic biomarkers of dementia disorders. We used a modified and sensitive detection method to analyze sAPPs levels in CSF in four groups of patients: AD (N = 33), MCI-AD (N = 17), non-AD dementia (N = 27), and disease controls (N = 19). Phosphorylated tau (p-tau), total tau, and Aβ42 were also analyzed using standard methods. A strong correlation was observed between sAPPα and sAPPβ, consistent with previous reports. Both sAPPα and sAPPβ were highly correlated with p-tau and total tau, suggesting that sAPPs
TY - JOUR. T1 - Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor. AU - Gillman, K.W.. AU - Starrett, J.E.. AU - Parker, M.F.. AU - Xie, K.. AU - Bronson, J.J.. AU - Marcin, L.R.. AU - McElhone, K.E.. AU - Bergstrom, C.P.. AU - Mate, R.A.. AU - Williams, Richard. AU - Meredith, J.E.. AU - Burton, C.R.. AU - Barten, D.M.. AU - Toyn, J.H.. AU - Roberts, S.B.. AU - Lentz, K.A.. AU - Houston, J.G.. AU - Zaczek, R.. AU - Albright, C.F.. AU - Decicco, C.P.. AU - Macor, J.E.. AU - Olson, R.E.. PY - 2010/6/10. Y1 - 2010/6/10. N2 - During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimers disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase ...
A method useful in the diagnosis of Alzheimers Disease in a patient in which an amyloid protein precursor (APP) substrate is combined with a sample of cerebrospinal fluid or blood obtained from the patient to be tested, and poteolytic cleavage of the APP substrate is detected. The absence of detectable proteolytic cleavage, or the detection of a substantially lesser degree of proteolytic cleavage, in the presence of the patients sample compared to that detected when an APP substrate is combined with test samples from control individuals, indicates affliction with Alzheimers Disease. Convenient test reagents and kits for aiding the diagnosis of Alzheimers Disease are provided, such as comprising an APP substrate and immunoreagents for detecting a fragment formed by proteolytic cleavage as well as chromogenic APP substrates.
In this study we analysed the influence of the Amyloid precursor protein (APP) interacting proteins on APP function, trafficking and processing in neuronal cells. Firstly, we examined the proposed interaction of APP, APLP1 and APLP2 with conventional kinesin. Previous studies reported that the cytoplasmic domain of APP exhibits high affinity binding with kinesin light chain (KLC). In context of this research project we provide evidence from GST-pull down analyses and co-immunoprecipitation studies that KLC does not interact directly with the cytoplasmic tail of APP, APLP1 or APLP2. Further, quantitative confocal analyses revealed that mutant APP lacking the APP intracellular domain were sorted, similar to wildtyp APP, to both, axons and dendrites. Thus, the intracellular domain and cytosolic interaction partners of APP/APLPs are not essential to mediate polarized transport in neurons. As the sorting of APP and APLP2 depend in non neuronal cells on the presence of the basolateral sorting signal ...
Neuritic plaques comprised of amyloid ß (Aß) are one of the primary neuropathological hallmarks of Alzheimers disease (AD). However, Aß plaque deposition is preceded by aberrations of the endosomal/lysosomal system, including abnormally enlarged endosomal compartments, accumulation of protease-resistant proteins, and atypical activation of the lysosomal system. The functional mechanisms accounting for these abnormalities have not yet been delineated. Towards our goal of identifying the proteins whose dysfunction contributes to the development of endosomal/lysosomal pathology in AD, we have found that: 1) proteins implicated in regulating late endosomal trafficking are among the targets of oxidation (carbonylation) in the brain of a presenilin 1/amyloid precursor protein (PS1/APP) transgenic mouse model of AD; 2) reduced neuronal expression of synaptic membrane protein HNK-1/NCAM is associated with Aß pathology in models of Aß deposition in cell culture and an amyloid precursor protein ...
Neuritic plaques comprised of amyloid ß (Aß) are one of the primary neuropathological hallmarks of Alzheimers disease (AD). However, Aß plaque deposition is preceded by aberrations of the endosomal/lysosomal system, including abnormally enlarged endosomal compartments, accumulation of protease-resistant proteins, and atypical activation of the lysosomal system. The functional mechanisms accounting for these abnormalities have not yet been delineated. Towards our goal of identifying the proteins whose dysfunction contributes to the development of endosomal/lysosomal pathology in AD, we have found that: 1) proteins implicated in regulating late endosomal trafficking are among the targets of oxidation (carbonylation) in the brain of a presenilin 1/amyloid precursor protein (PS1/APP) transgenic mouse model of AD; 2) reduced neuronal expression of synaptic membrane protein HNK-1/NCAM is associated with Aß pathology in models of Aß deposition in cell culture and an amyloid precursor protein ...
Product Name: Amyloid beta-Protein (Human, 34-40) Antiserum (50 ul vial) Product Number: NAB-14356-v Synonym(s): Amyloid beta-Protein (1-40) Specific Antiserum (Rabbit) Antiserum Application: Our undiluted antisera are suitable for immuno-histochemical use, for application to radioimmunoassay (RIA), or other non-isotop
The biologic relevance of AICD to APP physiology or AD pathology has been proposed, but in vivo evidence that supports the hypothesis has been lacking. The current study was aimed at examining this hypothesis by expressing AICD postnatally and selectively in the forebrain and hippocampal regions of mouse brain. Here, we first show that AICD is present in brain membranes from normal control mice and can be detected by Western blot alone. We further demonstrate that the transgenic mice that were generated in this study express AICD at levels that are similar to those found in APP transgenic mice with FAD mutation, which are two- to threefold higher than in nontransgenic mice. These data strongly support the validity of our mouse model, which was verified further by observing increased expression of KAI1 gene in transgenic mice. Finally, we present evidence that the AICD transgenic mice display robust changes in GSK-3 signaling, which supports an in vivo role for AICD.. The finding that an ...
Dysfunction and loss of synapses are early pathogenic events in Alzheimers disease (AD). A central step in the generation of toxic amyloid-β (Aβ) peptides is the cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme (BACE1). Here, we have elucidated whether down-regulation of septin (SEPT) protein family members, which are implicated in synaptic plasticity and vesicular trafficking, affects APP processing and Aβ generation. SEPT8 was found to reduce soluble APPβ and Aβ levels in neuronal cells via a post-translational mechanism leading to the decreased levels of BACE1 protein. In human temporal cortex, we identified alterations in the expression of specific SEPT8 transcript variants in relation to AD-related neurofibrillary pathology. These changes associated with altered β-secretase activity. We also discovered that the overexpression of a specific AD-associated SEPT8 transcript variant increased the levels of BACE1 and Aβ in neuronal cells. These changes were ...
The formation of senile plaques through amyloid-β peptide (Aβ) aggregation is a hallmark of Alzheimers disease (AD). Irrespective of its actual role in the synaptic alterations and cognitive impairment associated with AD, different therapeutic approaches have been proposed to reduce plaque formation. In rodents, daily intake of omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFAs) is required for neural development, and there is experimental and epidemiological evidence that their inclusion in the diet has positive effects on several neurodegenerative diseases. Similarly, estradiol appears to reduce senile plaque formation in primary mouse cell cultures, human cortical neurons and mouse AD models, and it prevents Aβ toxicity in neural cell lines. We previously showed that differences in dietary n-6/n-3 LC-PUFAs ratios modify the lipid composition in the cerebral cortex of female mice and the levels of amyloid precursor protein (APP) in the brain. These effects depended in part on the
Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid β protein (Aβ42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid β protein precursor (APP) transgenic mice, and plasma and brain levels of Aβ and the drug were evaluated. These studies show that (a) eight FDA-approved NSAIDs lower Aβ42 in vivo, (b) the ability of an NSAID to lower Aβ42 levels in cell culture is highly predicative of its in vivo activity, (c) in vivo Aβ42 lowering in mice occurs at drug levels achievable in humans, and (d) there is a significant correlation between Aβ42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Aβ42 levels ...
Alzheimer disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specfically the more amyloidogenic form, Abeta42. It was proposed that Abeta form Ca2+ permeable pores and bind to and modulate multiple synaptic proteins, including NMDAR, mGluR5 and VGCC, leading to the overfilling of neurons with calcium ions. Consequently, cellular Ca2+ disruptions will lead to neuronal apoptosis, autophagy ...
Reducing Akt-mediated huntingtin phosphorylation decreases APP accumulation at the synapse by reducing its anterograde axonal transport and ameliorates learning and memory in a mouse model of familial Alzheimer disease.
Alzheimers disease. Alzheimers disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques, which are generated through amyloid precursor protein (APP) cleavage, and neurofibrillary tangles, comprising paired helical filaments of intracellular, hyperphosphorylated tau, a microtubule-associated protein.. One of the first observations that suggested a role for altered autophagy in AD was the accumulation of autophagic vesicles in affected neurons (9, 10). While initially considered to represent increased autophagy, more recent evidence indicates that this accumulation is due to impaired autophagosome clearance. Presenilin-1 (PS1) is part of the γ-secretase complex required for Aβ production; however, it also functions to facilitate N-glycosylation of the V0a1 subunit of lysosomal vacuolar H+-ATPase (v-ATPase) and its trafficking to the lysosome to enable acidification of this organelle (11). PS1 and PS2 mutations cause familial autosomal-dominant AD (12-14) and result in amyloid ...