Abstract
Mutations in the presenilin proteins cause early-onset, familial Alzheimer's disease (FAD). We characterized the cellular localization and endoproteolysis of presenilin 2 (PS2) and presenilin 1 (PS1) in brains from 25 individuals with presenilin-mutations causing FAD, as well as neurologically normal individuals and individuals with sporadic Alzheimer's disease (AD). Amino-terminal antibodies to both presenilins predominantly decorated large neurons. Regional differences between the broad distributions of the two presenilins were greatest in the cerebellum, where most Purkinje cells showed high levels of only PS2 immunoreactivity. PS2 endoproteolysis in brain yielded multiple amino-terminal fragments similar in size to the PS1 amino-terminal fragments detected in brain. In addition, two different PS2 amino-terminal antibodies also detected a prominent 42 kDa band that may represent a novel PS2 form in human brain. Similar to PS1 findings, neither amino-terminal nor antiloop PS2 antibodies revealed substantial full-length PS2 in brain. Immunocytochemical examination of brains from individuals with the N141I PS2 mutation or eight different PS1 mutations, spanning the molecule from the second transmembrane domain to the large cytoplasmic loop domain, revealed immunodecoration of no senile plaques and only neurofibrillary tangles in the M139I PS1 mutation stained with PS1 antibodies. Overall presenilin expression and the relative abundance of full-length and amino-terminal fragments in presenilin FAD cases were similar to control cases and sporadic AD cases. Thus, accumulation of full-length protein or other gross mismetabolism of neither PS2 nor PS1 is a consequence of the FAD mutations examined.
Highlights
Presenilin 1 (PS1) and presenilin 2 (PS2) are broadly distributed, multimembrane-spanning proteins identified because of their role in familial, early-onset Alzheimer’s disease (FAD) [1,2,3]
The resulting antibodies were extensively characterized by Western blot analysis using overexpression systems prior to being used to detect the endogenous presenilins expressed in human brain
We have examined the expression, localization, and processing of both PS2 and presenilin 1 (PS1) in human brain
Summary
Presenilin 1 (PS1) and presenilin 2 (PS2) are broadly distributed, multimembrane-spanning proteins identified because of their role in familial, early-onset Alzheimer’s disease (FAD) [1,2,3]. Presenilins are localized to the secretory pathway, predominantly the endoplasmic reticulum (ER) [13,14,15,16]. This localization was confirmed by Lah and colleagues [6] for PS1 at the electron microscopic level in neurons from monkey brain. Mutations in the presenilin proteins cause early-onset, familial Alzheimer’s disease (FAD). Materials and Methods: We characterized the cellular localization and endoproteolysis of presenilin 2 (PS2) and presenilin 1 (PS1) in brains from 25 individuals with presenilin-mutations causing FAD, as well as neurologically normal individuals and individuals with sporadic Alzheimer’s disease (AD). Accumulation of full-length protein or other gross mismetabolism of neither PS2 nor PS1 is a consequence of the FAD mutations examined
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have