Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins

David R. Borchelt, Tamara Ratovitski, Judy Van Lare, Michael K. Lee, Vicki Gonzales, Nancy A. Jenkins, Neal G. Copeland, Donald L. Price, Sangram S. Sisodia

Research output: Contribution to journalArticlepeer-review

Abstract

Missense mutations in two related genes, termed presenilin 1 (PS1) and presenilin 2 (PS2), cause dementia in a subset of early-onset familial Alzheimer's disease (FAD) pedigrees. In a variety of experimental in vitro and in vivo settings, FAD-linked presenilin variants influence the processing of the amyloid precursor protein (APP), leading to elevated levels of the highly fibril-logenic Aβ1-42 peptides that are preferentially deposited in the brains of Alzheimer Disease (AD) patients. In this report, we demonstrate that transgenic animals that coexpress an FAD-linked human PSI variant (A246E) and a chimeric mouse/human APP harboring mutations linked to Swedish FAD kindreds (APP swe) develop numerous amyloid deposits much earlier than age-matched mice expressing APP swe and wild-type Hu PS1 or APP swe alone. These results provide evidence for the view that one pathogenic mechanism by which FAD-linked mutant PS1 causes AD is to accelerate the rate of β- amyloid deposition in brain.

Original languageEnglish (US)
Pages (from-to)939-945
Number of pages7
JournalNeuron
Volume19
Issue number4
DOIs
StatePublished - Oct 1997

ASJC Scopus subject areas

  • Neuroscience(all)

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