Enhanced amyloidogenic processing of the β-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer's disease mutations and a 'humanized' Aβ sequence

Andrew G. Reaume, David S. Howland, Stephen P. Trusko, Mary J. Savage, Diane M. Lang, Barry Greenberg, Robert Siman, Richard W. Scott

Research output: Contribution to journalArticle

Abstract

The processing of the β-amyloid precursor protein (APP) in vivo has been characterized in a novel animal model that recapitulates, in part, the APP genotype of a familial form of Alzheimer's disease (AD). A gene-targeting strategy was used to introduce the Swedish familial AD mutations and convert mouse Aβ to the human sequence. The mutant APP is expressed at normal levels in brain, and cleavage at the mutant β-secretase site is both accurate and enhanced. Furthermore, human Aβ production is significantly increased to levels 9-fold greater than those in normal human brain while nonamyloidogenic processing is depressed. The results on Aβ production extend similar findings obtained in cell culture to the brain of an animal and substantiate Aβ as a etiological factor in Swedish familial AD. These animals provide several distinguishing features over others created by conventional transgenic methodologies. The spatial and temporal expression patterns of human Aβ are expected to be faithfully reproduced because the gene encoding the mutant APP remains in its normal chromosomal context. Thus, the neuropathological consequences of human Aβ overproduction can be evaluated longitudinally in the absence of potential mitigating effects of APP overexpression or presence of the mouse Aβ peptide.

Original languageEnglish (US)
Pages (from-to)23380-23388
Number of pages9
JournalJournal of Biological Chemistry
Volume271
Issue number38
DOIs
StatePublished - Sep 30 1996
Externally publishedYes

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Bearings (structural)
Amyloid beta-Protein Precursor
Alzheimer Disease
Genes
Mutation
Processing
Brain
Animals
Mutant Proteins
Amyloid
Amyloid Precursor Protein Secretases
Gene encoding
Gene Targeting
Cell culture
Animal Models
Cell Culture Techniques
Genotype
Peptides

ASJC Scopus subject areas

  • Biochemistry

Cite this

Enhanced amyloidogenic processing of the β-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer's disease mutations and a 'humanized' Aβ sequence. / Reaume, Andrew G.; Howland, David S.; Trusko, Stephen P.; Savage, Mary J.; Lang, Diane M.; Greenberg, Barry; Siman, Robert; Scott, Richard W.

In: Journal of Biological Chemistry, Vol. 271, No. 38, 30.09.1996, p. 23380-23388.

Research output: Contribution to journalArticle

Reaume, Andrew G. ; Howland, David S. ; Trusko, Stephen P. ; Savage, Mary J. ; Lang, Diane M. ; Greenberg, Barry ; Siman, Robert ; Scott, Richard W. / Enhanced amyloidogenic processing of the β-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer's disease mutations and a 'humanized' Aβ sequence. In: Journal of Biological Chemistry. 1996 ; Vol. 271, No. 38. pp. 23380-23388.
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