Altered amyloid-β metabolism and deposition in genomic-based β-secretaee transgenic mice

Matthew J. Chiocco, Laura Shapiro Kulnane, Linda Younkin, Steve Younkin, Geneviève Evin, Bruce T. Lamb

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Amyloid-β (Aβ) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by β-secretase followed by γ-secretase cleavage. Identification of the primary β-secretase gene, BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering Aβ metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating β-secretase expression and activity alters APP processing and Aβ metabolism in vivo. Genomic-based BACE1 transgenic mice were generated that overexpress human BACE1 mRNA and protein. The highest expressing BACE1 transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice over-expressing both BACE1 and APP show specific alterations in APP processing and age-dependent Aβ deposition. We observed elevated levels of Aβ isofonns as well as significant increases of Aβ deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for β-secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation of BACE1 activity may play a significant role in AD pathogenesis in vivo.

Original languageEnglish (US)
Pages (from-to)52535-52542
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number50
DOIs
StatePublished - Dec 10 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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