Saturday, November 23, 2024
11/23/2024
Abstract/Project Summary The ultimate goal of this proposal is to understand the molecular and cellular substrates of early tau pathology, in order to create the foundation for future therapeutic targets for Alzheimer’s Disease (AD) and Alzheimer’s Disease Related Dementias (ADRD). Tau is a protein, expressed in neurons and oligodendroglial cells, whose aggregation is a pathological hallmark of a wide range of neurodegenerative diseases, including Fronto-Temporal-Dementia (FTD). Mounting evidence shows that the pathogenic process begins long before the detection of neuronal aggregates, with the detection of white matter changes in subjects with mild cognitive impairment, although the underlying pathogenic processes responsible for these changes remain only partially understood. This proposal will directly address this major gap of knowledge in the field, and tackle the major research priority of the 2019 NIH ADRD Summit, to investigate the early events of the disease. We leverage the expertise of the PI in biochemistry and phase separation and that of the co-I in myelin biology, to test the hypothesis that the white matter changes detected at the early stages of ADRD are mediated by misregulation of the condensed state of tau in oligodendrocytes. This hypothesis is motivated by the evidence that: 1) tau can self-assemble into a novel phase-separated condensed state (“condensate”); 2) tau mutations specific for FTD specifically impact tau condensates and 3) that oligodendroglial lineage cells, the myelin-forming cells of the central nervous system, are specific sites of tau-mediated dysfunction at the early stages of the neurodegenerative process. Extensive evidence in human subjects and animal models of FTD identify myelin damage and oligodendroglial dysfunction at the earliest stages of cognitive decline and support a model of neurodegeneration consequent to myelin pathology and occurring long before the detection of aggregates. Here we take an interdisciplinary biophysical and cellular approach that leverages expertise in tau biochemistry and glial biology, in order to test this hypothesis. In aim1 we will develop quantitative metrics for defining tau condensates – a crucial advance necessary for understanding how tau condensates are modulated. In aim 2 we will determine the influence of tau pathological variants and myelin protein and lipids on tau condensate properties. In aim 3 we shall examine the role of endogenously expressed and exogenously uptaken tau and tau variants in oligodendrocyte lineage cells at specific stages of differentiation. Together, results from this work will illuminate the role of tau condensates in oligodendrocytes and further our knowledge of the events occurring at the early stages of tau pathology.
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