Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY/ABSTRACT Alzheimer's disease is a progressive, age-related, degenerative brain disease. The most notable symptom is a significant cognitive impairment accompanying a substantial loss of dendritic spines and, eventually, neurons themselves. Since these end-stages are mostly irreversible, it is critical to identify appropriate molecular targets for intervention before the synaptic dysfunction and neuronal loss become permanent. Brains with Alzheimer's disease display the presence of increased protein accumulations, such as intracellular tau inclusions (neurofibrillary tangles) and extracellular beta-amyloid deposits (senile plaques). However, alterations in synaptic structure, function, and plasticity appear before these pathologies arise in various Alzheimer's disease models, highlighting the pathological significance of early-stage synaptic alterations, potentially driven by Alzheimer's disease-associated proteins, as a proximal event in Alzheimer's disease etiology. Importantly, it is now widely accepted that local protein synthesis plays essential roles in neurons and, in particular, that key components of protein synthesis subserving synapses and synaptic plasticity take place in dendrites, in association with dendritic spines, the cellular site of synaptic plasticity. These observations lead us to hypothesize that pathogenic forms of tau specifically interfere with dendritic protein synthesis and that this effect contributes to the pathologic features seen in Alzheimer's disease. We propose to test this hypothesis by taking advantage of tau pathology model mice and a novel suite of genetically encodable molecular tools implementable in these animals to address dendritic protein synthesis in the hippocampus. Successful completion of this project will enrich our understanding of how tau pathology leads to early synaptic dysfunction in Alzheimer's disease. Ultimately, these studies will provide molecular insights into target molecules for intervention before the irreversible loss of synapses and neurons in Alzheimer's disease and related dementia.
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