Alzheimer's disease: clues from flies and worms.
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Presenilin mutations give rise to familial Alzheimer's disease and result in elevated production of amyloid beta peptide. Recent evidence that presenilins act in developmental signalling pathways may be the key to understanding how senile plaques, neurofibrillary tangles and apoptosis are all biochemically linked. (+info)
Dynamics of plaque formation in Alzheimer's disease.
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Plaques that form in the brains of Alzheimer patients are made of deposits of the amyloid-beta peptide. We analyze the time evolution of amyloid-beta deposition in immunostained brain slices from transgenic mice. We find that amyloid-beta deposits appear in clusters whose characteristic size increases from 14 microm in 8-month-old mice to 22 microm in 12-month-old mice. We show that the clustering has implications for the biological growth of amyloid-beta by presenting a growth model that accounts for the experimentally observed structure of individual deposits and predicts the formation of clusters of deposits and their time evolution. (+info)
Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease.
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The brains of Alzheimer's disease patients contain extracellular Abeta amyloid deposits (senile plaques). Although genetic evidence causally links Abeta deposition to the disease, the mechanism by which Abeta disrupts cortical function is unknown. Using triple immunofluorescent confocal microscopy and three-dimensional reconstructions, we found that neuronal processes that cross through an Abeta deposit are likely to have a radically changed morphology. We modeled the electrophysiological effect of this changed morphology and found a predicted delay of several milliseconds over an average plaque. We propose that this type of delay, played out among thousands of plaques throughout neocortical areas, disrupts the precise temporal firing patterns of action potentials, contributing directly to neural system failure and dementia. (+info)
Age-related changes in the brain of the dog.
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Although many age-related changes have been described in the nervous system of different species, few authors have specifically studied the topic. Knowledge of such changes is essential to veterinary pathologists, who must distinguish the lesions of specific pathologic processes from those arising as a result of normal aging. The brains of 20 old dogs, ranging in age from 8 to 18 years, were compared with those of 10 young dogs using routine staining techniques (hematoxilin and eosin, periodic acid-Schiff), special staining techniques (periodic acid-methenamine silver stain), and immunohistochemical techniques to detect glial fibrillary acid protein, neurofilaments, ubiquitin, and beta-amyloid. Changes affected meninges and choroid plexuses, meningeal and parenchymal vessels, neurons, and glial cells. Of special interest was the presence of polyglucosan bodies, cerebrovascular amyloid deposition, senile plaques, and ubiquitinated bodies. Some of the age-related changes found, particularly lipofuscin, polyglucosan bodies, and beta-amyloid protein deposition, may play a role in the pathogenesis of the canine cognitive dysfunction syndrome. The dog could be used as a natural animal model for the study of normal aging and human neurodegenerative diseases. (+info)
Histochemically reactive zinc in plaques of the Swedish mutant beta-amyloid precursor protein transgenic mice.
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Endogenous metals such as zinc may contribute to beta-amyloid (Abeta) aggregation and hence the plaque formation. In the present study, we examined brains of four Swedish mutant amyloid precursor protein (APP) transgenic mice at 12 months of age for histochemically reactive zinc in the plaques. Here, we report that all the Congo red (+) mature plaques contained chelatable zinc, as demonstrated by staining with the zinc-specific fluorescent dye 6-methoxy-8-quinolyl-para-toluenesulfonamide (TSQ). On the other hand, Congo red (-) preamyloid Abeta deposits were not stained with TSQ. Interestingly, although cerebellum contained similar degree of preamyloid Abeta deposits as cerebral cortex, it was completely devoid of Congo red- or TSQ-stained mature plaques. Although zinc from plaques was only slowly and partially removed by a specific zinc remover, dithizone, treatment of brain sections with heparinase-III, which degrades heparan sulfate proteoglycan (HSPG), another major constituent of plaques, greatly fastened the zinc removal with dithizone. The present study has demonstrated the presence of histochemically reactive zinc in plaques, but not preamyloid Abeta deposits, of the Swedish mutant APP transgenic mice. Because preamyloid Abeta deposits fail to develop into congophilic plaques in cerebellum where synaptic vesicle zinc is deficient, the synaptic zinc may be a necessary element in the plaque formation. In holding zinc inside plaques, HSPG may contribute in addition to Abeta. (+info)
Association of microglia with amyloid plaques in brains of APP23 transgenic mice.
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Microglia are a key component of the inflammatory response in the brain and are associated with senile plaques in Alzheimer's disease (AD). Although there is evidence that microglial activation is important for the pathogenesis of AD, the role of microglia in cerebral amyloidosis remains obscure. The present study was undertaken to investigate the relationship between beta-amyloid deposition and microglia activation in APP23 transgenic mice which express human mutated amyloid-beta precursor protein (betaPP) under the control of a neuron-specific promoter element. Light microscopic analysis revealed that the majority of the amyloid plaques in neocortex and hippocampus of 14- to 18- month-old APP23 mice are congophilic and associated with clusters of hypertrophic microglia with intensely stained Mac-1- and phosphotyrosine-positive processes. No association of such activated microglia was observed with diffuse plaques. In young APP23 mice, early amyloid deposits were already of dense core nature and were associated with a strong microglial response. Ultrastructurally, bundles of amyloid fibrils, sometimes surrounded by an incomplete membrane, were observed within the microglial cytoplasm. However, microglia with the typical characteristics of phagocytosis were associated more frequently with dystrophic neurites than with amyloid fibrils. Although the present observations cannot unequivocally determine whether microglia are causal, contributory, or consequential to cerebral amyloidosis, our results suggest that microglia are involved in cerebral amyloidosis either by participating in the processing of neuron-derived betaPP into amyloid fibrils and/or by ingesting amyloid fibrils via an uncommon phagocytotic mechanism. In any case, our observations demonstrate that neuron-derived betaPP is sufficient to induce not only amyloid plaque formation but also amyloid-associated microglial activation similar to that reported in AD. Moreover, our results are consistent with the idea that microglia activation may be important for the amyloid-associated neuron loss previously reported in these mice. (+info)
The AMY antigen co-occurs with abeta and follows its deposition in the amyloid plaques of Alzheimer's disease and down syndrome.
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Novel plaque-like "AMY" lesions were recently described in the brains of patients with Alzheimer's disease (AD). Using three Abeta antibodies, we now document the co-occurrence of AMY immunoreactivity (IR) with amyloid beta-peptide (Abeta) in the large majority of plaques in AD brain. AMY IR was detected in many compacted plaques, whereas its co-localization with early, diffuse Abeta deposits was rare. AMY IR overlapped considerably or fully with Abeta and, in more severely affected AD brains, decorated the periphery of some plaques. In a temporal series of 29 Down syndrome (DS) brains from patients aged 12 to 73 years, the earliest AMY IR was detected in some plaques at age 15, following the earliest appearance of Abeta plaques (age 12 years), and then accrued within a subset of Abeta deposits, namely, the more spherical, compacted plaques. Brains from DS patients 29 years and older showed AMY staining in many Abeta plaques, as seen in AD. Brains from eight monkeys aged 17 to 34 years and thirty APP transgenic mice aged 8 to 20 months showed Abeta IR but no AMY IR. We conclude that AMY IR represents an amyloid-associated antigen that co-deposits in most but not all Abeta plaques in AD and DS and that accumulation of the AMY antigen follows Abeta deposition in plaques. (+info)
Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis.
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One mechanism leading to neurodegeneration during Alzheimer's disease (AD) is amyloid beta peptide (Abeta) neurotoxicity. Abeta elicits in cultured central nervous system neurons a biphasic response: a low-dose neurotrophic response and a high-dose neurotoxic response. Previously we reported that NF-kappaB is activated by low doses of Abeta only. Here we show that NF-kappaB activation leads to neuroprotection. In primary neurons we found that a pretreatment with 0.1 microM Abeta-(1-40) protects against neuronal death induced with 10 microM Abeta-(1-40). As a known neuroprotective agent we next analyzed the effect of tumor necrosis factor alpha (TNF-alpha). Maximal activation of NF-kappaB was found with 2 ng/ml TNF-alpha. Pretreatment with TNF-alpha protected cerebellar granule cells from cell death induced by 10 microM Abeta-(1-40). This protection is described by an inverted U-shaped dose response and is maximal with a NF-kappaB-activating dose. The molecular specificity of this protective effect was analyzed by specific blockade of NF-kappaB activation. Overexpression of a transdominant negative IkappaB-alpha blocks NF-kappaB activation and potentiates Abeta-mediated neuronal apoptosis. Our findings show that activation of NF-kappaB is the underlying mechanism of the neuroprotective effect of low-dose Abeta and TNF-alpha. In accordance with these in vitro data we find that nuclear NF-kappaB immunoreactivity around various plaque stages of AD patients is reduced in comparison to age-matched controls. Taken together these data suggest that pharmacological NF-kappaB activation may be a useful approach in the treatment of AD and related neurodegenerative disorders. (+info)