Increased in vivo amyloid-?42 production, exchange, and loss in presenilin mutation carriers.

ABSTRACT: Alzheimer's disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-? (A?) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of A?42 compared to A?40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers. We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related noncarriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of A? isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer Pittsburgh compound B (PIB). CNS A?42 to A?40 production rates were 24% higher in mutation carriers compared to noncarriers, and this was independent of fibrillar amyloid deposits quantified by PET PIB imaging. The fractional turnover rate of soluble A?42 relative to A?40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of A?42 into plaques, leading to reduced recovery of A?42 in cerebrospinal fluid (CSF). Reversible exchange of A?42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that A?42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble A?42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in A?42 concentrations in the CSF.

SUBMITTER: Potter R 

PROVIDER: S-EPMC3838868 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature