Tau-Induced Astrocyte Senescence: A Novel Mechanism for Neuronal Dysfunction in Alzheimer’s Disease

Abstract

Chronic sterile inflammation is a pathological feature of Alzheimer’s disease (AD) and other neurodegenerative diseases. The mechanisms that drive neuroinflammation and its impact on AD progression are still incompletely understood. The accumulation of molecular damage in somatic cells can trigger cellular senescence, an irreversible state of cell cycle arrest accompanied by the expression of proinflammatory mediators known collectively as the “senescence-associated secretory phenotype” (SASP). Misfolded tau forms pathogenic soluble aggregates that are released extracellularly and are transmitted trans-neuronally, promoting native tau phosphorylation and aggregation in target cells. We recently showed that, in addition to neurons, pathogenic soluble extracellular tau aggregates propagate to brain microvascular endothelial cells, where microtubule destabilization triggers senescence/SASP. Because astrocytes have a critical role in the regulation of both synaptic function and cerebral blood flow and are directly exposed to tau at its site of release at the tripartite synapse, we conducted studies to define whether soluble aggregated tau propagates to astrocytes, inducing astrocyte senescence/SASP and neuronal dysfunction/damage. Our studies indicate that tau can be propagated transcellularly to astrocytes, triggering cellular senescence/SASP. Our studies suggest that astrocyte senescence is detrimental to dendritic and synaptic structure and density, suggesting that pathogenic soluble tau-induced astrocyte senescence may contribute to synaptic dysfunction and loss in AD. Drugs that eliminate senescent cells are FDA-approved and antibody-based approaches to remove tau from brain are already in clinical trials. Our studies suggest that these interventions could be effective in the treatment of AD and other tauopathies.

Reactive and Senescent Astroglial Phenotypes as Hallmarks of Brain Pathologies

“…It has been shown that the clearance of senescent astrocytes from a mouse model of tau-dependent ND prevented the degeneration of cortical and hippocampal neurons and preserved cognitive function [216]. Recently, it has also been reported that tau is responsible for astrocyte senescence, which further contributes to synaptic dysfunction and neuronal loss in AD [217]. In addition, tau has a direct role in the induction of astrocyte senescence, probably through p53 activation [207].…”

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

“…Interestingly, studies from the 1970s observed that lithium was a MSA, raising interesting questions about its established antiviral and neuroprotective properties ( Matsunaga et al., 2015 ; Murru et al., 2020 ; Chen et al., 2021 ). Indeed, lithium reverses pTau-induced astrocytic senescence and enhances T-cell function, suggesting senolytic properties ( Bhattacharyya and Wolff, 1976 ; Kucharz et al, 1988 ; Olson et al., 2019 ; Viel et al., 2020 ). This is significant, as lithium can reverse the virus-induced damage of tubulin, a key molecule in T cell activation ( Kopf and Kiermaier, 2021 ).…”