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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034924-05
Application #
8699615
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Petanceska, Suzana
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Strittmatter, Stephen M (2018) Emerging Mechanisms in Alzheimer's Disease and Their Therapeutic Implications. Biol Psychiatry 83:298-299
Salazar, Santiago V; Cox, Timothy O; Lee, Suho et al. (2018) Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-? Induced Synaptic Dysfunction and Loss. J Neurosci :
Kent, Brianne A; Strittmatter, Stephen M; Nygaard, Haakon B (2018) Sleep and EEG Power Spectral Analysis in Three Transgenic Mouse Models of Alzheimer's Disease: APP/PS1, 3xTgAD, and Tg2576. J Alzheimers Dis 64:1325-1336
Nygaard, Haakon B; Erson-Omay, E Zeynep; Wu, Xiujuan et al. (2018) Whole Exome Sequencing of an Exceptional Longevity Cohort. J Gerontol A Biol Sci Med Sci :
Brody, A Harrison; Strittmatter, Stephen M (2018) Synaptotoxic Signaling by Amyloid Beta Oligomers in Alzheimer's Disease Through Prion Protein and mGluR5. Adv Pharmacol 82:293-323
Smith, Levi M; Zhu, Rong; Strittmatter, Stephen M (2018) Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model. Neuropharmacology 130:54-61
Kostylev, Mikhail A; Tuttle, Marcus D; Lee, Suho et al. (2018) Liquid and Hydrogel Phases of PrPC Linked to Conformation Shifts and Triggered by Alzheimer's Amyloid-? Oligomers. Mol Cell 72:426-443.e12
Klein, Zoe A; Takahashi, Hideyuki; Ma, Mengxiao et al. (2017) Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. Neuron 95:281-296.e6
Salazar, Santiago V; Strittmatter, Stephen M (2017) Cellular prion protein as a receptor for amyloid-? oligomers in Alzheimer's disease. Biochem Biophys Res Commun 483:1143-1147
Heiss, Jacqueline K; Barrett, Joshua; Yu, Zizi et al. (2017) Early Activation of Experience-Independent Dendritic Spine Turnover in a Mouse Model of Alzheimer's Disease. Cereb Cortex 27:3660-3674

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