However, recent understanding of the complexity of the processing of APP by γ-secretase and the effects of FAD mutations on this processing suggest other forms of Aβ as potentially pathogenic.
In the present study, we aimed to evaluate its possible beneficial effects in a well-established preclinical mixed model of familial Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) based on the use of transgenic APPswe/PS1dE9 (APP/PS1) mice fed with a high fat diet (HFD).
We have tested the functional significance of BACE1 processing of APP using App-Swedish (App<sup>s</sup> ) knock-in rats, which carry an App mutation that causes familial Alzheimer's disease (FAD) in humans.
These findings demonstrate that in mice expressing FAD-linked PS1, microglia play a critical role in the regulation of EE-dependent AHNPC proliferation and neurogenesis and the modulation of affective behaviors.<b>SIGNIFICANCE STATEMENT</b> Inheritance of mutations in genes encoding presenilin 1 (PS1) causes familial Alzheimer's disease (FAD).
These data suggest that in the FAD PS1 ΔE9 cells, the elevated cellular cholesterol level contributes to the altered APP processing by increasing APP localized in lipid rafts.
We conclude that fAD mutations most likely reduce the stability of the protein-substrate complex and thus retention time of APP-C99, leading to premature release of longer toxic Aβ<sub>42</sub> in accordance with the FIST model of Aβ production, whereas the observed general destabilization of the protein may reduce activity towards other substrates.
Single-point mutations in the genes coding for amyloid precursor protein (APP) and presenilin 1 (PS1), the active subunit of γ-secretase that cleaves APP to produce Aβ, are the main causes of rare but severe familial Alzheimer's disease (fAD).
Causative mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) account for a majority of cases of familial Alzheimer disease (FAD) inherited in an autosomal-dominant pattern.
Autosomal-dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (<i>PSEN1</i>), presenilin 2 (<i>PSEN2</i>), and amyloid precursor protein (<i>APP</i>).
Mutations in the presenilin1 (PSEN1) cause familial Alzheimer's disease (FAD), providing a special opportunity to study pre-symptomatic individuals who would be predicted to develop Alzheimer's disease (AD) in the future.
These data suggest that in the FADPS1ΔE9 cells, the elevated cellular cholesterol level contributes to the altered APP processing by increasing APP localized in lipid rafts.
By generating novel tools for measuring Ca<sup>2+</sup> in living cells, and combining different approaches, we showed that FAD-linked PS2 mutants significantly alter cell Ca<sup>2+</sup> signaling and brain network activity, as summarized below.
Dermal fibroblasts were obtained from a 55 year old male Сaucasian familial Alzheimer's disease (AD) patient carrying heterozygous V717I mutation in the APP gene.