Here, we report that the expression of FAD-linked PS1 M146V mutant affects store-operated calcium channel activity (Isoc) in human neuroblastoma SK-N-SH cells.
We investigated the association between TOMM40 rs10524523, 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.
Here, we have aimed to determine (i) whether this phenotype is present in heterozygous PS1 KI(M146V) mice, which reflects more accurately the PS1 FAD condition in humans and (ii) whether Abeta(1-42), which is invariably present in the PS1 FAD brain and is thought to affect neuronal cell cycle kinetics, may contribute to the abnormal cell cycle/cell death phenotype seen in PS1 KI(M146V) mice.
Specifically we find that either over-expression or FAD mutation in presenilin 1 (M146L and M146V) leads to chromosome missegregation and aneuploidy in vivo and in vitro: (1) Up to 20% of lymphocytes and neurons of FAD-PS-1 transgenic and knocking mice are aneuploid by metaphase chromosome analysis and in situ hybridization.
To investigate the factors that drive the Abeta42/Abeta40 ratio and amyloid pathogenesis and to investigate the possible interactions between wild-type and FAD mutant PS1, which are co-expressed in transgenic animals, we expressed the PS1 M146V knock-in allele either on wild-type PS1 (PS1M146V/+) or PS1 null (PS1M146V/-) background and crossed these alleles with the Tg2576 APP transgenic mice.
To investigate the pathogenic mechanism of PS1 mutations linked to FAD, we established inducible mouse neuroblastoma (Neuro 2a) cell lines expressing the human wild-type (wt) or mutated PS1(M146L or deltaexon 10) under the control of the Lac repressor.
We now document that, in the brains of transgenic mice, the absolute amounts of accumulated N- and C-terminal derivatives generated from the FAD-linked PS1 variants in which Glu replaces Ala at codon 246 (A246E) or Leu replaces Met at codon 146 (M146L) accumulate to a significantly higher degree (approximately 40-50%) than the fragments derived from wild-type PS1.