We conclude that altered C99 interactions are a common feature of diverse types of PS1FAD mutants and that also patients with Aβ43-generating FAD mutations could in principle be treated by GSMs.
Familial Alzheimer's disease (FAD) mutations within the catalytic subunit protein of presenilin 1 (PS1) decrease γ-cleavage, resulting in the generation of toxic, long Aβs.
Familial Alzheimer's disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-β (Aβ) peptides.
Generation of one iPSC line (IMEDEAi006-A) from an early-onset familial Alzheimer's Disease (fAD) patient carrying the E280A mutation in the PSEN1 gene.
As presenilin is the catalytic component of the γ-secretase protease complex that produces Aβ from APP, mutation of the enzyme or substrate that produce Aβ leads to FAD.
Rare cases of early-onset familial Alzheimer's diseases are caused by high-penetrant mutations in genes coding for amyloid precursor protein, presenilin 1, and presenilin 2.
APP mRNA translation inhibitors such as the anticholinesterase phenserine, and high throughput screened molecules, selectively inhibited the uniquely folded iron-response element (IRE) sequences in the 5'untranslated region (5'UTR) of APP mRNA and this class of drug continues to be tested in a clinical trial as an anti-amyloid treatment for AD.
To test this, we isolated EVs from iPSC-derived neuronal cultures generated from an fAD patient harboring a A246E mutation to presenilin-1 and stereotactically injected these EVs into the hippocampi of wild-type C57BL/6 mice.
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.