There is increasing evidence for soluble Amyloid-beta peptide (Abeta) uptake into neurons being an early event in the pathogenesis of Alzheimer's Disease (AD). Identification of the early events leading to neurotoxicity is key to preventing or curing Alzheimer's disease. In this proposal, we examine a very specific, receptor-mediated mechanism of Abeta uptake into neurons.
Aim 1 will examine the role of the Low Density Lipoprotein Receptor Related Protein (LRP) in mediating Transforming Growth Factor-beta2 (TGFbeta2) targeting of Abeta to neurons. TGFbeta2 has been shown to be upregulated in AD brain and recent evidence points to TGFbeta2 being upregulated very early in the course of the disease.
In Aim 1 we will investigate the mechanism by which TGFbeta2 impacts Abeta uptake, clearance and degradation. Another protein known to be genetically linked to AD is Apolipoprotein E (ApoE).
Aim 2 examines the role of ApoE, an LRP ligand, in TGFbeta2-mediated targeting of Abeta to neurons.
Aim 3 completes the protocol by testing our mechanism in vivo using human ApoE transgenics and ApoE knockout mice.
The Aims outlined in the proposal utilize primary cell cultures, organotypic hippocampal slice cultures (OHSC) and in vivo methods, giving us a symmetrical and powerful approach to studying receptor-mediated uptake and neurotoxicity of Abeta. Another advantage to our mouse infusion model of AD is that, as opposed to transgenic models that overproduce Abeta, we can dissect Abeta clearance away from issues of Abeta production in our mouse infusion model of Alzheimer's disease. There are few published reports that focus on receptor-mediated pathways for Abeta toxicity in Alzheimer's Disease. Understanding this mechanism may help to resolve the paradox that """"""""Abeta plaque deposition is not sufficient to cause Alzheimer's"""""""" and could lead to new and better targets of intervention in Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-3 (01))
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Snyder, Stephen D
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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