Accelerated plaque accumulation, associative learning deficits, and up-regulation of α7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins

Kelly Dineley, Xuefeng Xia, Duy Bui, J. David Sweatt, Hui Zheng

Research output: Contribution to journalArticle

188 Scopus citations

Abstract

Familial Alzheimer's disease-associated mutations in presenilin 1 or 2 or amyloid precursor protein result in elevated β-amyloid, β-amyloid accumulation, and plaque formation in the brains of affected individuals. By crossing presenilin 1 transgenic mice carrying the A246E mutation with plaque-producing amyloid precursor protein K670N/M671L transgenic mice (Tg2576), we show that co-expression of both mutant transgenes results in acceleration of amyloid accumulation and associative learning deficits. At 5 months of age with no detectable plaque pathology, amyloid precursor protein transgenic animals are impaired in contextual fear learning following two pairings of conditioned and unconditioned stimuli but appear normal following a more robust five-pairing training. At 9 months of age when β-amyloid deposition is evident, these mice are impaired following both two-pairing and five-pairing protocols. Mice carrying both transgenes are impaired in contextual fear conditioning at either age. All transgenic animal groups performed as well as controls in cued fear conditioning, indicating that the contextual fear learning deficits are hippocampus-specific. The associative learning impairments are coincident with elevated α7 nicotinic acetylcholine receptor protein in the dentate gyrus. These findings provide two robust and rapid assays for β-amyloid-associated effects that can be performed on young animals: impaired contextual fear learning and up-regulation of β7 nicotinic receptors.

Original languageEnglish
Pages (from-to)22768-22780
Number of pages13
JournalJournal of Biological Chemistry
Volume277
Issue number25
DOIs
StatePublished - Jun 21 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry

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