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Increased in vivo amyloid-β42 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-β (Aβ) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 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 Aβ 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 Aβ42 to Aβ40 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 Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques, leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). Reversible exchange of Aβ42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Potter R,Patterson BW,Elbert DL,Ovod V,Kasten T,Sigurdson W,Mawuenyega K,Blazey T,Goate A,Chott R,Yarasheski KE,Holtzman DM,Morris JC,Benzinger TL,Bateman RJ

doi

10.1126/scitranslmed.3005615

subject

Has Abstract

pub_date

2013-06-12 00:00:00

pages

189ra77

issue

189

eissn

1946-6234

issn

1946-6242

pii

5/189/189ra77

journal_volume

pub_type

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Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers.