Accelerated Amyloid Deposition in the Brains of Transgenic Mice Coexpressing Mutant Presenilin 1 and Amyloid Precursor Proteins

Author:

Borchelt, D. R.

Ratovitski, T.

Vanlare, J.

Lee, M. K.

Gonzales, V.

Jenkins, N. A.

Copeland, N. G.

Price, D. L.

Sisodia, S. S.
Author Address

Copeland NG JOHNS HOPKINS UNIV SCH MED DEPT PATHOL BALTIMORE, MD 21205 USA JOHNS HOPKINS UNIV SCH MED DEPT PATHOL BALTIMORE, MD 21205 USA JOHNS HOPKINS UNIV SCH MED DEPT NEUROSCI BALTIMORE, MD 21205 USA JOHNS HOPKINS UNIV SCH MED DEPT NEUROL BALTIMORE, MD 21205 USA NCI FREDERICK CANC RES & DEV CTR ABL BASIC RES PROGRAM MAMMALIAN GENET LAB FREDERICK, MD 21702 USA

Abstract:

Missense mutations in two related genes, termed presenilin 1 (PS1) and presenilin 2 (PS2), cause dementia in a subset of early-onset familiar Alzheimer's disease (FAD) pedigrees. In a variety of experimental in vitro and in vivo settings, PAD-linked presenilin variants influence the processing of the amyloid precursor protein (APP), leading to elevated levels of the highly fibrillogenic A beta 1-42 peptides that are preferentially deposited in the brains of Alzheimer Disease (AD) patients. In this report, we demonstrate that transgenic animals that coexpress an PAD-linked human PS1 variant (A246E) and a chimeric mouse/human APP harboring mutations linked to Swedish PAD 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 PAD-linked mutant PS1 causes AD is to accelerate the rate of beta-amyloid deposition in brain. [References: 51]

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