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.
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.
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 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.
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>).
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.
APP, whose mutations cause familial Alzheimer's disease (FAD), modulates neurotransmission via interaction of its cytoplasmic tail with the synaptic release machinery.
In old transgenic mice expressing mutated human (APP<sup>SwInd</sup>) linked to Familial Alzheimer's Disease, with both expression of APP<sup>SwInd</sup> and plaques, the rate and destination of Mn<sup>2+</sup> axonal transport is altered, as detected by time-lapse manganese-enhanced magnetic resonance imaging (MEMRI) of the brain in living mice.
To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer's disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein).
Gene mutations within amyloid precursor protein (APP or AβPP) and/or presenilin 1 (PS1) genes are determinants of familial Alzheimer's disease (fAD) and remain fundamental for experimental models.