Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. Neuron
(Impact Factor: 15.05).
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.
Available from: Carme Auladell
- "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. "
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ABSTRACT: The pathogenesis of Alzheimer Disease (AD) is characterized by accumulation of β-amyloid protein in the brain (in both soluble and insoluble forms) and by the presence of intracellular neurofibrillary tangles (NFTs), leading to neurotoxicity. The exact mechanisms whereby Aβ triggers brain alterations are unclear. However, accumulating evidence suggests that a deregulation of Ca(2+) signaling may play a major role in disease progression. Calcium-buffering proteins, including calbindin-D28K (CB), calretinin (CR) and parvalbumin (PV), may offer neuroprotection by maintaining calcium homeostasis. Although marked reductions in these proteins have been observed in the brains of mice and humans with AD, their contribution to AD pathology remains unclear. The aim of the present study was to analyze distribution patterns of CB(+,) CR(+) and PV(+) interneurons in different areas of the hippocampus, a brain region that is severely affected in AD. A transgenic knock-in APPswe/PS1dE9 mouse model of familial AD was used. The data were obtained from the brains of 3- and 12- month-old animals. These ages roughly correspond to an early mature adult (prior to clinical manifestations) and a late middle-age (clinical symptoms readily detectable) phase in human AD patients. Immunostaining revealed increases in CB and PV immunoreactivity (IR) in hippocampus of 3-month-old transgenic mice, compared to wild-type animals. Possibly, these proteins are upregulated in an attempt to control cellular homeostasis and synaptic plasticity. However, the pattern of CB-IR was reversed in 12-month-old animals, potentially indicating a loss of cellular capacity to respond to pathophysiological processes. In addition, at this age, a noticeable increase in PV-IR was observed, suggesting the presence of hippocampal network hyperactivity in older AD-like mice. Our results indicate that CaBP(+) neuronal subpopulations play a role in adult neurogenesis and in AD pathology, particularly at early disease stages, suggesting that these neurons may serve as potential predictors of future AD in non-demented individuals.
Copyright © 2015. Published by Elsevier Inc.
Available from: Keiko Unno
- "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. "
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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.
Available from: Stefan J. Marciniak
- "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 , . "
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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.
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