Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.
ABSTRACT Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Abeta1-42(43)/Abeta1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Abeta1-42(43)/Abeta1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Abeta peptides terminating at 42(43), species that foster Abeta deposition.
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ABSTRACT: The effects of soybean extracts were investigated in senescence-accelerated (SAMP10) mice, a mouse model of brain senescence with cognitive dysfunction. Mature soybeans are usually yellow. However, the green soybean retains green color after being ripened. Cognitive functions were significantly better-preserved in aged mice fed green soybean than age-matched control mice with or without yellow soybean feeding. Molecular mechanisms of the beneficial effect of green soybean on brain functions were examined through transcriptome analysis of SAMP10 hippocampus. The high expression of Ptgds was significantly associated with green soybean diet, which encodes lipocalin-type prostaglandin D2 synthase, a putative endogenous amyloid β(Αβ)-chaperone. In consonance, Aplp1 expression was significantly reduced, a member of amyloid precursor proteins. Furthermore, the amount of Aβ 40 and 42 was reduced in the insoluble fraction of cerebral cortex. These results suggest that the intake of green soybean ameliorates cognitive dysfunction of aged mice through the reduction of Aβ accumulation.
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ABSTRACT: Presenilins play essential roles in memory formation, synaptic function, and neuronal survival. Mutations in the Presenilin-1 (PSEN1) gene are the major cause of familial Alzheimer's disease (FAD). How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI) mice carrying the FAD mutation L435F or C410Y. Remarkably, KI mice homozygous for either mutation recapitulate the phenotypes of Psen1(-/-) mice. Neither mutation altered Psen1 mRNA expression, but both abolished γ-secretase activity. Heterozygosity for the KI mutation decreased production of Aβ40 and Aβ42, increased the Aβ42/Aβ40 ratio, and exacerbated Aβ deposition. Furthermore, the L435F mutation impairs hippocampal synaptic plasticity and memory and causes age-dependent neurodegeneration in the aging cerebral cortex. Collectively, our findings reveal that FAD mutations can cause complete loss of Presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism. Copyright © 2015 Elsevier Inc. All rights reserved.Neuron 03/2015; 85(5):967-81. DOI:10.1016/j.neuron.2015.02.010 · 15.98 Impact Factor
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ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most frequent cause of dementia in elderly people. Current therapies are directed against the symptoms and at best slow down the progress of the disease in some cases. Thus, it is of particular importance to find drugs focusing on the origins of AD. Recent studies indicate that soluble oligomers (up to 12mers and higher) of Aβ1−42 are highly neurotoxic at nanomolar levels and probably a major cause for the symptoms of AD. Furthermore, structural similarity was found between the oligomers of several amyloidogenic proteins. A compound that inhibits Aβ aggregation in AD may therefore prevent aggregation in other amyloid diseases as well, with little or no modification to the compounds. These findings indicate that inhibition of oligomer aggregation is an appealing approach for AD drug research. In this study, we show the effects of a library of 18 chemical compounds, based on a 2-pyridone structure which is known to interfere with Aβ assembly, on the formation of oligomers. These molecules fulfil Lipinski’s rule of 5 and thereby should readily pass the blood brain barrier after application. Oligomers of Aβ1−42 were prepared in the absence and presence of these compounds and identified using Western blotting, dot blotting and atomic force microscopy. The toxicity of these preparations was determined by applying them onto neural cell lines and measuring the cell viability with MTT, WST-1 and resazurin based assays. The results indicate that several compounds decreased neurotoxicity of the oligomeric preparations by inhibition of aggregation. Despite the high variation in toxicity between the individual preparations we identified a compound offering both, low toxicity and stable oligomerization inhibiting potency, which will serve as a lead molecule for further development. Also we demonstrate an impact of the applied oligomerization protocol on cell viability. After further optimization we hope our method will prove to be a useful method for screening drug candidates directed against Aβ oligomers.09/2007, Degree: Magister rer. nat., Supervisor: Johannes Berger