A variety of gene products have been implicated in the pathogenesis of dementias of the Alzheimer type (DAT), the most common forms of dementias in the elderly. A key unsolved problem has been how these several proteins may interact to cause the two major types of pathology, deposits of beta amyloid (Ab) and the collections of abnormal forms of tau protein, the main constituent of neurofibrillary tangles (NFT). The present proposal addresses the potential role of an adaptor protein called FE65 in such interactions. FE65p (FE65 protein) binds to an intracellular domain of the precursor protein (bPP) of Ab and to several other proteins. When overexpressed, it increases the rate of bPP trafficking and Ab production. Our new evidence [using FE65 (FE65 gene) knockout mice] also supports a role for FE65 in the regulation of the expression of a kinase implicated in the altered phosphorylation of tau protein (glycogen synthase kinase-3b or tau protein kinase I) (GSK-3b). We have also found cytochemical evidence for the co-localization of FE65p with tau in DAT brains. Using our FE65 knockout mice, we now propose to investigate the mechanisms whereby FE65 regulates expression of GSK-3b and several other candidate genes. We suggest that this regulation is via CP2/LBP-1/LSF (CP2) transcription elements, since FE65p directly binds to CP2. We will also investigate the role of FE65 on Ab production/deposition and the rate of bPP internalization, using FE65 knockout mice and knockout mice crossed with the Tg2576 line, which overexpress a familial DAT mutant bPP.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG019711-04
Application #
6789398
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Snyder, Stephen D
Project Start
2001-09-30
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$327,456
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Martin, George M (2012) Stochastic modulations of the pace and patterns of ageing: impacts on quasi-stochastic distributions of multiple geriatric pathologies. Mech Ageing Dev 133:107-11
Martin, George M (2011) The biology of aging: 1985-2010 and beyond. FASEB J 25:3756-62
Cool, Bethany H; Chan, Guy C-K; Lee, Lin et al. (2010) A flanking gene problem leads to the discovery of a Gprc5b splice variant predominantly expressed in C57Bl/6J mouse brain and in maturing neurons. PLoS One 5:e10351
Cool, Bethany H; Zitnik, Galynn; Martin, George M et al. (2010) Structural and functional characterization of a novel FE65 protein product up-regulated in cognitively impaired FE65 knockout mice. J Neurochem 112:410-9
Martin, George M; Bergman, Aviv; Barzilai, Nir (2007) Genetic determinants of human health span and life span: progress and new opportunities. PLoS Genet 3:e125
Zitnik, Galynn; Wang, Lin; Martin, George M et al. (2007) Localizations of endogenous APP/APP-proteolytic products are consistent with microtubular transport. J Mol Neurosci 31:59-68
Yang, Zheng; Cool, Bethany H; Martin, George M et al. (2006) A dominant role for FE65 (APBB1) in nuclear signaling. J Biol Chem 281:4207-14
Maezawa, Izumi; Hong, Hyun-Seok; Wu, Hui-Chuan et al. (2006) A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-beta oligomeric complexes. J Neurochem 98:57-67
Hu, Qubai; Wang, Lin; Yang, Zheng et al. (2005) Endoproteolytic cleavage of FE65 converts the adaptor protein to a potent suppressor of the sAPPalpha pathway in primates. J Biol Chem 280:12548-58
Martin, George M (2005) Genetic modulation of senescent phenotypes in Homo sapiens. Cell 120:523-32

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