Increased ABeta production or accumulation is considered major factors in the development of Alzheimer's disease (AD). ApoE4 dosage, considered a major risk factor for Alzheimer's disease, increases ABeta40 accumulation by reducing Abeta degradation, while presenilin mutations increase the risk of Alzheimer's disease by increasing Abeta production. The mechanism of ABeta-toxicity in vivo is not well understood, and a lack of consistent correlation between ABeta-deposits and dementia further confounds the issue. An understanding of how A is degraded will help understand how it can be toxic in vivo. In preliminary experiments, inhibition of lysosomal degradation of ABeta increases both neuronal Abeta staining and toxicity in vivo, whereas a decrease in extracellular ABeta deposits using multiple approaches sometimes reduces acute toxicity. This proposal will test the hypothesis if endosomal/lysosomal ABeta accumulation can cause direct neurotoxicity, while extracellular ABeta leads to neurotoxicity secondary to inflammation. A lipoprotein carrier based ABeta infusion model will be used to obtain widespread AB deposits and neurotoxicity.
Aim 1 will test the hypothesis if limiting intracellular degradation with inhibitors of cathepsins D or B will increase intracellular accumulation of AB and induce toxicity by endosomal/lysosomal leakiness, cathepsin upregulation, and caspase activation.
In Aim 2, extracellular degradation of ABeta will be inhibited to test the hypothesis if extracellular ABeta accumulation and deposition causes less acute neurotoxicity associated with inflammation.
Aim 3 will test if lipoprotein carrier protein deletions that limit the receptor-mediated uptake of ABeta increase extracellular deposition but reduce intracellular ABeta accumulation and neurotoxicity.
Aim 4 will evaluate if age-related defects in intracellular degradation increase ABeta accumulation and toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG016793-01A2
Application #
6200078
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Snyder, D Stephen
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$189,000
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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