Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system characterized by progressive loss of cognitive skills and associated with neuropathologic features including amyloid deposits and neurofibrillary tangles. Although the etiology of AD is most likely multifactorial, including environmental factors, some families show a clear pattern of autosomal dominant transmission and such cases are referred to as familial AD (FAD). Recently a gene called S182 or presenilin corresponding to the FAD locus on chromosome 14 was cloned. More than 20 different mutations in this gene have now been identified. The goal of this proposal is to generate an animal model of FAD.
The specific aims are: 1. Make a PS1 transgenic animal using PS1 with the rat neuron-specific enolase promotor. A normal PS1 clone, Met146leu, or ala246-glu mutation forms of PS1 will be used. 2. Introduce pro267ser into the endogenous mouse PS1 gene using homologous recombination. 3. A knock-in approach will be used to introduce human PS1 with the glu280ala mutation into exon 3 of the mouse gene. 4. Develop human-specific antibodies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014392-02
Application #
2683178
Study Section
Special Emphasis Panel (ZRG1-NEUC (02))
Program Officer
Oliver, Eugene J
Project Start
1997-04-01
Project End
2001-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Wen, Paul H; Friedrich Jr, Victor L; Shioi, Junichi et al. (2002) Presenilin-1 is expressed in neural progenitor cells in the hippocampus of adult mice. Neurosci Lett 318:53-6
Wen, Paul H; Shao, Xiang; Shao, Zhiping et al. (2002) Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice. Neurobiol Dis 10:8-19