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.
"They show age-dependent cognitive deficits due to the increased cerebral levels of the highly fibrillogenic Aβ42 peptide. In this model around the age of 6 months, senile plaques are readily detectable (Borchelt et al., 1996; van Groen et al., 2006; Wirths et al., 2008). Fig. 3. Distribution pattern of CB-IR neurons in different areas of the hippocampus of 3-month-old APPswe/PS1dE9 mice vs wild-type. "
"The level of Αβ in the cerebral cortex was measured using ELISA kits, human/rat β amyloid (40) ELISA kit Wako II and human/rat β amyloid (42) ELISA kit Wako, high sensitive (Wako Pure Chemical Industries, Osaka, Japan). Brain samples were prepared as described in Zhang et al. (2011) and Borchelt et al. (1996) with some modifications. Approximately 100 mg of cerebral cortex were homogenized at 4 °C in 1 ml of RIPA buffer (Wako Pure Chemical Industries) in the presence of protease inhibitor cocktail (Sigma-Aldrich, St. Louis, MO, USA) for the measurement of Αβ in the soluble fraction. "
[Show abstract][Hide abstract] 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.
"Normally, Aβ peptides are predominantly 40 amino acids in length (Aβ40), while 5–10% have a further 2 amino acids at the C-terminus (Aβ42). The bulk of cases of FAD can be accounted for by mutations that either increase the total amount of Aβ , , or favour the production of longer, more aggregation-prone, isoforms of the peptide . FAD has been reported to be a consequence of variation in the sequence or copy number of either the APP gene, or the genes PSEN1 or PSEN2 encoding catalytic subunits of γ-secretase , . "
[Show abstract][Hide abstract] ABSTRACT: The human Aβ peptide causes progressive paralysis when expressed in the muscles of the nematode worm, C. elegans. We have exploited this model of Aβ toxicity by carrying out an RNAi screen to identify genes whose reduced expression modifies the severity of this locomotor phenotype. Our initial finding was that none of the human orthologues of these worm genes is identical with the genome-wide significant GWAS genes reported to date (the "white zone"); moreover there was no identity between worm screen hits and the longer list of GWAS genes which included those with borderline levels of significance (the "grey zone"). This indicates that Aβ toxicity should not be considered as equivalent to sporadic AD. To increase the sensitivity of our analysis, we then considered the physical interactors (+1 interactome) of the products of the genes in both the worm and the white+grey zone lists. When we consider these worm and GWAS gene lists we find that 4 of the 60 worm genes have a +1 interactome overlap that is larger than expected by chance. Two of these genes form a chaperonin complex, the third is closely associated with this complex and the fourth gene codes for actin, the major substrate of the same chaperonin.
PLoS ONE 07/2014; 9(7):e102985. DOI:10.1371/journal.pone.0102985 · 3.23 Impact Factor
Juliana B Hoppe, Christianne G Salbego, Helena Cimarosti
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