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 #
5R01AG034924-03
Application #
8305546
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
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$326,111
Indirect Cost
$129,065
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Onorati, Marco; Li, Zhen; Liu, Fuchen et al. (2016) Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Rep 16:2576-92
Haas, Laura T; Salazar, Santiago V; Kostylev, Mikhail A et al. (2016) Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer's disease. Brain 139:526-46
Heiss, Jacqueline K; Barrett, Joshua; Yu, Zizi et al. (2016) Early Activation of Experience-Independent Dendritic Spine Turnover in a Mouse Model of Alzheimer's Disease. Cereb Cortex :
Smith, Levi M; Strittmatter, Stephen M (2016) Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity. Cold Spring Harb Perspect Med :
Haas, Laura T; Strittmatter, Stephen M (2016) Oligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease. J Biol Chem 291:17112-21
Salazar, Santiago V; Strittmatter, Stephen M (2016) Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease. Biochem Biophys Res Commun :
Kaufman, Adam C; Salazar, Santiago V; Haas, Laura T et al. (2015) Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann Neurol 77:953-71
Kostylev, Mikhail A; Kaufman, Adam C; Nygaard, Haakon B et al. (2015) Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models. J Biol Chem 290:17415-38
Strittmatter, Stephen M (2014) Overcoming Drug Development Bottlenecks With Repurposing: Old drugs learn new tricks. Nat Med 20:590-1
Haas, Laura T; Kostylev, Mikhail A; Strittmatter, Stephen M (2014) Therapeutic molecules and endogenous ligands regulate the interaction between brain cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5). J Biol Chem 289:28460-77

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