The salient pathological feature of Alzheimer's Disease (AD) is the presence of a high density of amyloid plaques in the brain tissue of AD victims. The plaques are predominantly composed of human beta-amyloid peptide (betaA4) a 39-42 mer whose neurotoxicity appears to be related to its aggregation. While the exact origin of the betaA4 in these plaques remains uncertain, betaA4 appears to be made by most if not all cells in the CNS, and is present in normal human CSF at a concentration of 10.10M. The primary thrust of the present proposal is to explore the aggregation, deposition and binding characteristics of low, physiological concentrations of betaA4 (10,10M). The key to the present proposal is our development of a novel radioiodinated ~A4 which will allow us for the first time to examine the characteristics of this molecule and its related fragments at concentrations similar to that found in normal human CSF. Using physiological concentrations of the radioiodinated betaA4 we will examine; the characteristics, kinetics and factors affecting I3A4 aggregation and disaggregation in a tissue free system; the characteristics, kinetics and factors affecting betaA4 deposition onto tissue sections of AD and normal human brain; the characteristics of betaA4 binding to tissue sections of adult rat brain and the neonatal rat; the characteristics and kinetics of betaA4 binding to specific populations of cultured neurons and glia: and the correlation between the in vitro toxicity of betaA4 aggregates and their aggregation/disaggregation characteristics. These studies will provide an understanding of the characteristics of betaA4 self-aggregation and deposition at physiological concentrations of betaA4. Understanding the factors influencing the aggregation and deposition of physiological concentrations of betaA4 should provide new insight into the amyloidosis that occurs in AD. Since aggregates of betaA4 are neurotoxic to cells within the CNS, this work may lead to a new understanding and treatment for the dementia in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG011852-01A1
Application #
2053084
Study Section
Neurology C Study Section (NEUC)
Project Start
1994-09-10
Project End
1997-06-30
Budget Start
1994-09-10
Budget End
1995-06-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Psychiatry
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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