Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD.

ABSTRACT: Alzheimer disease (AD) is characterized by progressive memory loss, reduction in cognitive functions, and damage to the brain. The ?-amyloid precursor protein can be sequentially cleaved by ?- secretase and ?-secretase. Mutations in the presenilin1(PS1) are the most common cause of Familial Alzheimer's disease (FAD). PS1 mutations can alter the activity of ?-secretase on the cleavage of the ?-amyloid precursor protein, causing increased A? production. Previous studies show that the ?APP-C-terminal fragment is first cleaved by ?-scretase, primarily generating long fragments of A?48 and A?49, followed by the stepwise cleavage of every three amino acid residues at the C terminus, resulting in A?48-, 45-, 42 line and A?49-, 46-, 43-, 40 line. Here, we used LC-MS/MS to analyze unique peptides IAT, VVIA, ITL, TVI, IVI through sequential cleavage, combined with ELISA to test the level of A?42 and A?40 for validation. The results show that most FAD mutant PS1 can alter the level of A?42 and A?40 monitored by the A?42/A?40 ratio. Among them, six mutants (I143T, H163P, S170F, Q223R, M233V, and G384A) affect the A?42/40 ratio through both A?49-40 and A?48-38 lines; L166P through decreasing the A?49-40 line, six mutants (I143V, M146V, G217A, E280A, L381V, and L392V) through increasing the A?48-42 line. More importantly, we found some mutations can affect the ?-secretase cleavage preference of ?-CTF and ?-CTF. In conclusion, we found that the FAD PS1 mutations mainly increase the generation of A?42 by decreasing the cleavage of A?42-A?38 and A?43-A?40.

SUBMITTER: Li N 

PROVIDER: S-EPMC4786568 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature