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 language | English (US) |
|---|---|
| Pages (from-to) | 939-945 |
| Number of pages | 7 |
| Journal | Neuron |
| Volume | 19 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 1997 |
Bibliographical note
Funding Information:The work is dedicated to Ms. Debbie Swing, to whom we are greatly indebted for her technical assistance in creating the transgenic mice described in this study. We thank Dr. Dale Shenk (Athena Neurosciences, South San Francisco, CA) for the generous gift of 10D5 Aβ antibodies and Drs. Heline Barelli and Frederic Checler for the generous gift of 3540 and 3543 Aβ antibodies. We thank Drs. Juan Troncoso and Lee Martin for critical review of neuropathological materials and for helpful discussion. We are grateful to the Alzheimer's Association (D. R. B.) and the Develbiss Fund for funding to support the APP swe transgenic mouse colony. This work was supported by the U. S. Public Health Service, National Institutes of Health grants NIH AG05146, NS 20471, and AG14248; the Adler Foundation; and the National Cancer Institute, DHHS, under contract with Advanced Bioscience Laboratories (N. A. J. and N. G. C.).