Alzheimer's disease (AD) is one of the largest unmet medical need today. Epidemiologic data indicate that this need will mushroom in the coming decade unless new therapeutic options are identified. Pathological and human genetic studies have made substantial progress in supporting an """"""""Amyloid Hypothesis"""""""" of AD and efforts to remove amyloid-A? (A?) immunologically, to block A? production by secretases and enhance A? degradation are advancing. However, a cell biological understanding of how A? is toxic for neurons has lagged. Recent studies have focused attention on soluble oligomers of A? as culprits in the disease process in both correlative and functional studies. The neuronal targets by which oligomeric A? mediates neuronal dysfunction are unknown but their identification would provide a novel pathway in drug development. In Preliminary Studies, we have identified the cellular Prion Protein (PrPC) as an A?-oligomer receptor by expression cloning. Synaptic responsiveness in brain slices from young adult PrP null mice is normal, but the A?-oligomer blockade of long-term potentiation (LTP) is absent. Thus, PrPC is a mediator of A?- oligomer induced synaptic dysfunction in vitro. Here, we will determine if the same molecular interaction plays a role in A?-induced memory dysfunction and neurodegeneration. We will determine the requirements for specificity in this interaction and explore downstream signaling pathways. Together, this work holds the promise of validating a novel therapeutic target for AD, one that is based not on A? levels but on preventing the deleterious actions of A?-oligomers on neurons through a specific binding site.

Public Health Relevance

Alzheimer's disease extracts a massive health care burden but there are few treatments. Molecular studies have revealed that the amyloid- ? peptide plays a key role in the brain malfunction. In this project, we test the hypothesis that cellular Prion protein mediates amyloid- ? action. If validated, this hypothesis predicts that Prion protein will be a novel target for therapeutic development for Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034924-02
Application #
8118159
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Refolo, Lorenzo
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$326,111
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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