PSEN2 mutation at codon 214 for predicting a valine to leucine substitution was found in a 70-year-old woman, who showed a dementia of the Alzheimer type.
A novel premature termination mutation supports loss of function or haploinsufficiency as pathogenic mechanisms in presenilin 2 associated Alzheimer's disease.
A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease.
A significant member of early-onset familial type of Alzheimer's disease cases has been shown to be caused by dominant mutations in either of the two genes encoding presenilin 1 (PS1) and presenilin 2 (PS2).
About 1% of Alzheimer's Disease (AD) cases have an early-onset autosomal dominant familial form of the disease, genetic analyses of which have found three causal genes: amyloid beta-protein precursor (AbetaPP), presenilin 1 (PS1) and presenilin 2 (PS2).
Accumulation of Aβ could be caused by increased production, as indicated by several mutations in the amyloid precursor protein or the γ-secretase components presenilin-1 and presenilin-2 that cause familial early-onset AD.
Although the mechanism(s) whereby the PS-1 and PS-2 gene mutations operate remains unclear, it seems from the present study that the effect of the PS-2 gene mutation on the brain is much less severe, at least as far as Abeta deposition is concerned, than that of the PS-1 mutation, which seems to confer a much earlier and a much more aggressive development of AD.
Amyloid precursor protein, presenilin 1 and presenilin 2 genes have been identified as causative genes for familial AD, whereas apolipoprotein E epsilon4 allele has been associated to the risk for late onset AD.
An increased production of Abeta-42 by mutation of PS2 genes promotes caspase expression and is associated with the Cox-2 found in the brain of AD patients.