Tau-induced astrocyte senescence in Alzheimer's disease

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Contact PD/PI: Galvan, Veronica ABSTRACT Health and function of the nervous system relies on astrocytes, the most abundant glial cell in the mammalian brain. Astrocytes are integral components of brain architecture, and critically regulate brain function and plasticity through dynamic interactions with synapses. Accumulation of abnormally phosphorylated tau protein in astrocytes is common in aging and is exacerbated in Alzheimer's disease (AD). In AD, hyper-phosphorylated tau in neurons detaches from microtubules to form soluble aggregates, destabilizing the microtubule cytoskeleton. Pathogenic soluble tau aggregates (also called tau oligomers) are then released and transfer trans- neuronally, promoting tau aggregation and destabilization of the microtubule cytoskeleton in target cells. Aging contributes the largest biological risk for AD; yet the mechanisms that link aging to AD remain elusive. The development of cellular senescence and the accumulation of senescent cells during aging compromises tissue function. Senescent astrocytes accumulate in AD brain. We discovered that, similar to trans-neuronal propagation, soluble pathogenic tau aggregates are transmitted to astrocytes, where they potently trigger microtubule destabilization and cellular senescence. The functional impact of tau transmission to astrocytes, and its contribution to AD, however, remain unexplored. Our central hypotheses are that: (a) tau-induced astrocyte senescence is a key driver of neuronal dysfunction and cognitive decline in AD, and (b) removal of pathogenic tau or senescent astrocytes will treat AD-related dysfunction in a surrogate model of AD by restoring neuronal function. We propose two Specific Aims. Aim 1 will define how tau transmission causes astrocyte senescence, and will identify heterogeneous subtypes of senescent astrocytes and their secreted factors in a surrogate model of AD tauopathy; Aim 2 will (a) establish the therapeutic potential of pathogenic tau or senescent cell removal in AD-related neuronal and cognitive dysfunction, (b) determine, in human brains, how accumulation of astrocyte tau and of senescent astrocytes is linked to molecular abnormalities identified in Aim 1 during AD progression; and (c) define the incidence of heterogeneous subtypes of senescent astrocytes identified in Aim 1 in human AD. This work will address, for the first time, the involvement of tau-induced astrocyte senescence in AD etiology, and will markedly advance knowledge of how pathogenic tau (and the cellular events it triggers) and senescence itself can be targeted therapeutically. By singling out astrocyte senescence as a novel mechanism of AD-like pathogenesis in mice, we will open up a completely new avenue of investigation in AD. Because tau immunotherapy is being advanced in the clinic and the senolytics we will use are FDA-approved, our results could have rapid translational potential, contributing new and urgently needed tools to treat AD and potentially other dementias. Project Summary/Abstract Page 7