Synaptic pathology has increasingly become recognized as a principle feature of Alzheimer's disease (AD) and occurs prior to the traditional hallmarks of AD, namely amyloid plaques and neurofibrillary tangles (NFT). Notably, our research group was the first to observe synapse loss in human AD brain. Loss of dendritic spines has been observed in young mouse models of AD before the buildup of plaques and NFT, and also correlates much better with cognitive loss. At a molecular level, several studies have demonstrated that Ap peptides, particularly Ap oligomers, potently inhibit hippocampal long-term potentiation (LTP). Our recent published results indicate that Ap causes endocytosis of NMDA and AMPA glutamate receptors, processes that are likely linked to perturbation of synaptic plasticity and remodeling of dendritic spines. In unpublished work, we have found that the kinase, Cdk5 (previously implicated in AD), regulates dendritic spine morphology via phosphorylation of WAVE1 (a regulator of actin polymerization), and that Ap may regulate WAVE1 phosphorylation and level of expression. Our observations strongly suggest that Ap-mediated glutamate receptor endocytosis and morphological changes or loss of dendritic spines in cortical and hippocampal neurons may contribute to the earliest stages of memory impairment. Moreover, our unpublished results suggest that synaptic dysfunction resulting from increased Ap levels is reversible, thus offering the possibility of alleviating cognitive defects in AD and related diseases. In the proposed studies, we will further investigate the effects of Ap on synaptic structure, transmission and plasticity. We propose to characterize the effect of Ap monomers, oligomers and fibrils on dendritic spines (AimI) as well as glutamate receptor endocytosis (Aim II). We will investigate the role of Cdk5, WAVE1 (as a new substrate of Cdk5) and CK1 (as a collaboration with Project 2) in Ap-induced spine loss (Aim I). In addition we propose to investigate the role of STEP, dephosphorylation of NR2B and GluR1, and Cdk5-WAVE1 in Ap-induced glutamate receptor endocytosis (Aim II). Furthermore, we will investigate whether cholinesterase inhibitors affect glutamate receptor localization (Aim II).We also propose to characterize the effects of Ap on synaptic plasticity and on learning and memory. We will examine the effect of Ap lowering agents on glutamate receptor endocytosis in vivo(Aim II). Finally, we will use Ts65Dn (Down syndrome mouse model) as well as AD mouse models (as a collaboration with Project 2) to investigate Ap-induced synaptic plasticity and behavioral abnormality (Aim III). Taken together, these studies will elucidate the molecular mechanism(s) leading to synaptic pathology in AD and provide potential targets for AD therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Rockefeller University
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