We discuss how TREM2 may control the microglial response to Aβ and its impact on microglial senescence, as well as the interaction of TREM2 with other molecules that are encoded by gene variants associated with AD and the hypothetical consequences of the cleavage of TREM2 from the cell surface.
Gene expression profiling of peripheral blood leukocytes shows consistent longitudinal downregulation of TOMM40 and upregulation of KIR2DL5A, PLOD1, and SLC2A8 among fast progressors in early Alzheimer's disease.
We investigated the association between TOMM40rs10524523, age of onset, and memory performance in patients with the PSEN1 M146L mutation in a large familial Alzheimer's disease Calabrian kindred, with a wide variability of onset not attributable to APOE.
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.