Increasing evidence points to a causative role for amyloid beta-peptide (Abeta) in the pathogenesis of Alzheimer's disease (AD). Thus, mechanisms through which Abeta affects cellular properties have come under intensive study. We have identified a novel Abeta binding protein Alcohol Dehydrogenase termed ABAD, with properties of a beta- hydroxyacyl-Co-enzyme A dehydrogenase and a generalized alcohol dehydrogenases, which is expressed at high levels in AD-affected brain. Recombinant ABAD binds Abeta (1-40/42) specifically, via the N- terminus (residues 1-20). ABAD, associated with endoplasmic reticulum (ER) and mitochondria functions as a co-factor in Abeta-induced cell stress; co-transfection of cells with constructs driving over-expression of betaAPP(V717G) and wild-type (wt) ABAD caused generation of reactive aldehydes and induction of DNA fragmentation in COS and neuroblastoma cells. In contrast, similar co-transfection studies with constructs encoding betaAPP(V717G) and mutationally-inactivated ABAD(Y168G/K172G) did not result in cytotoxicity. We propose that under quiescent conditions ABAD contributes to neuronal homeostasis, but in an Abeta-rich environment, the intact enzyme acquires pathogenic properties, exacerbating cell stress and cytotoxicity. In view of increased levels of ABAD in neurons in AD brain, we will prepare transgenic (Tg) mice with targeted over-expression of ABAD in neurons, using the thy-1 promoter, and analyze their response to an Abeta-rich environment provided by cross-breeding with Tb mice over-expressing variant betaAPP. The biologic implications of ABAD for the neuronal stress response will be further probed by over-expressing a dominant-negative form of ABAD in Tg mice, thereby selectively deleting ABAD function in neurons. In each case, mice will be analyzed for neuropathologic, electrophysiologic, biochemical and behavioral endpoints, as well as in terms of their response to ischemic stress.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
2P50AG008702-11A1
Application #
6344467
Study Section
Special Emphasis Panel (ZAG1-PKN-7 (J1))
Project Start
1989-09-29
Project End
2002-05-31
Budget Start
Budget End
Support Year
11
Fiscal Year
2000
Total Cost
$271,393
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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