Little is unknown about the mechanisms involved in the regulation of neuronal network activity by the microtubule associated protein tau, a key pathogenic protein in Alzheimer's disease (AD). The long term goal is to develop an independent career as a neuropathologist and a molecular neuroscientist integrating observations from human neuropathology with molecular understanding to gain new insights into AD pathogenesis and therapeutic strategies. This research is initially focused on how tau regulates neuronal activity and how this regulation relates to mechanisms of AD. Preliminary studies show tau localization is regulated by homeostatic scaling, a critical form of synaptic plasticity implicated in AD. The overall objectives for this application are to (i) elucidate the role of tau in homeostatic scaling, (ii) define alterations in the molecular interactions of tau during homeostatic scaling, and (iii) determine the role of homeostatic scaling in the post-synaptic alterations of tau and AMPA receptors in culture models of AD. The central hypothesis of this proposal is that homeostatic scaling pathways are regulated by tau and are utilized by A? to create post- synaptic changes in AD. This hypothesis will be tested using live neuron fluorescent imaging of tau and AMPA receptors, inhibition or knock-down of tau and proteins critical to homeostatic scaling, and mass spectrometry analysis of tau interacting proteins under homeostatic scaling conditions. The rationale for this project is that improved understanding of tau functions and their relationship to the pathogenesis of AD may lead to new avenues of investigation for AD therapies while offering an opportunity to establish the candidate's independence as a molecular neuroscientist. This effort will directly involve the mentorship of Dr. Richard Huganir, an expert neuroscientist in the field of molecular mechanisms synaptic plasticity, and will take advantage of the rich and collaborative environment of Alzheimer's disease research at Johns Hopkins University. This work will build on the candidate's strong foundation in neurodegenerative disease pathology and research, which will be supplemented by training in synaptic biology, imaging techniques, human induced pluripotent stem cells (iPSCs), and biostatistical analysis, areas critical to the proposed work and to future investigations. The proposed research is innovative because it defines novel roles and interactions of tau regulated by neuronal activity, and it directly tests the contribution of homeostatic scaling to AD-related synaptic changes. The proposed research is significant because it will provide insight into novel biologic functions and interactions of tau, and their relationship to AD pathogenesis. Ultimately, knowledge of these mechanisms may elucidate of the contribution of tau to sporadic AD and lead to novel therapeutic strategies.
The proposed research is relevant to public health because it investigates the normal and disease-related functions of tau, a key protein involved in Alzheimer's disease. This research will contribute to our knowledge of mechanisms of sporadic Alzheimer's disease and may lead to new therapeutic strategies to treat this devastating disease. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to seeking knowledge about the behavior of living systems and application of that knowledge to reduce illness and disability.
