Mutations in the presenilin 1 (PS1) and presenilin 2 genes cosegregate with the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. We now document that the Aβ1-42(43)/Aβ1-40 ratio in the conditioned media of independent N2a cell lines expressing three FAD-linked PS1 variants is uniformly elevated relative to cells expressing similar levels of wild-type PS1. Similarly, the Aβ 1-42(43)/Aβ1-40 ratio is elevated in the brains of young transgenic animals coexpressing a chimeric amyloid precursor protein (APP) and an FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or transgenic mice coexpressing wild-type human PS1 and APP. These studies provide compelling support for the view that one mechanism by which these mutant PS1 cause AD is by increasing the extracellular concentration of Aβ peptides terminating at 42(43), species that foster Aβ deposition.
Bibliographical noteFunding Information:
We thank Mr. Marek Fischer and Dr. Charles Weissmann for the pPrPHG plasmid, which contained a modified murine prion protein gene from which the MoPrP. Xho vector was generated. We also thank Ms. Debbie Swing for her technical assistance in the production of transgenic mice and Mr. Yuri McKee, Ms. Liesl Awalt, Ms. Luba Romansteva, and Mr. Dustin Englekin for help in screening transgenic mice. We thank Drs. Mary Savage and Barry Greenberg (Cephalon, Inc.) for their collaborative efforts during the early stages of the cell culture studies. This work was supported by the U. S. Public Health Service, National Institute of Health grants NIH AG05146, NS 20471 (S. S. and D. L. P.); AG05689 (M. S.); AG11508 and AG09464 (S. E. G.); P01AG14633-01, AG12685-04, and AG06656 (S. G. Y); and by grants from the Adler Foundation (G. T. and S. S. S.), the Develbiss Fund (D. R. B., D. L. P., and S. S. S.), and the Alzheimer's Association (D. R. B. and S. S. S.) and the National Cancer Center Institute, DHHS, under contract with Advanced Bioscience Laboratories. D. L. P. is the recipient of a Javitz Neuroscience Investigator Award (NIH NS10580); D. L. P and D. R. B are the recipients of a Leadership and Excellence in Alzheimer's Disease (LEAD) Award (NIH AG07914); S. S. S. is the recipient of an Alzheimer's Association Zenith Award.