Genetic study of familial cases of Alzheimer's disease (original) (raw)
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Journal of Neurochemistry, 2005
Gene knockout studies in mice suggest that presenilin 1 (PS1) is the major γ-secretase and that it contributes disproportionately to amyloid β (Aβ) peptide generation from β-amyloid precursor protein (APP), whereas PS2 plays a more minor role. Based on this and other observations we hypothesized that familial Alzheimer's disease (FAD) mutations in PS2 would have a dramatic effect on function in order to have an observable effect on Aβ levels in the presence of normal PS1 alleles. Only four of the eight reported FAD mutations in PS2 have altered function in vitro suggesting that the other variants represent rare polymorphisms rather than disease-causing mutations. In support of our hypothesis, the four verified PS2 FAD mutations cause substantial changes in the Aβ 42/40 ratio, comparable with PS1 mutations that cause very-early-onset FAD. Most of the PS2 mutations also cause a significant decrease in Aβ 40, APP C-terminal fragment (CTF)γ and Notch intracellular domain (NICD) production suggesting that they are partial loss of function mutations. PS2 M239V, its PS1 homolog M233V, and other FAD mutations within transmembrane (TM) 5 of PS1 differentially affect CTFγ and NICD production suggesting that TM5 of PS are important for γ-secretase cleavage of APP but not Notch.
Presenilin-1 mutation E318G and familial Alzheimer's disease in the Italian population
Neurobiology of Aging, 2007
Presenilin-1 (PSEN-1) is a component of the g-secretase complex involved in b-amyloid precursor protein (bAPP) processing. To date about 140 pathogenic mutations in the PSEN-1 gene have been identified and their main biochemical effect is to increase the production of the fibrillogenic peptide Ab(1–42). An exception is the PSEN-1 [E318G] mutation that does not alter Ab(1–42) generation and is generally considered a non-pathogenic polymorphism. Nevertheless, this mutation was reported to be a genetic risk factor for familial Alzheimer’s disease (FAD) in the Australian population. To independently confirm this indication, we performed a case-control association study in the Italian population. We found a significant association (p < 0.05, Fisher’s exact test) between the presence of PSEN-1 [E318G] and FAD. In addition, on measuring the Ab(1–42) and Ab(1–40) concentrations in fibroblast-conditioned media cultured from PSEN-1 [E318G] carriers and PSEN-1 [wild type] controls we noted a significant decrease (p <0.05, Mann–Whitney test) in the Ab(1–42)/Ab(1–40) ratio in PSEN-1 [E318G] carriers, suggesting a peculiar biochemical effect of this mutation.