Tau protein aggregation induces cellular senescence in the brain.

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer9s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others. Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss, yet the mechanisms mediating tau toxicity are poorly understood. NFT-containing neurons do not die, which suggests secondary mechanisms are driving toxicity. We evaluated gene expression patterns of NFT-containing neurons microdissected from AD patient brains and found they develop an expression profile consistent with cellular senescence described in dividing cells. This complex stress response induces a near permanent cell cycle arrest, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Moreover, senescent cells induce chronic degeneration of surrounding tissue through the secretion of pro-inflammatory, pro-apoptotic molecules termed the senescence-associated secretory phenotype (SASP). Using transgenic mouse models of tau-associated pathogenesis we found that NFTs induced a senescence-like phenotype including DNA damage, karyomegaly, mitochondrial dysfunction and SASP. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT load. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, senolytic treatment reduced total NFT burden, neuron loss and ventricular enlargement; and normalized cerebral blood flow to that of non-transgenic control mice. Collectively, these findings indicate that NFTs induce cellular senescence in the brain, which contributes to neurodegeneration and brain dysfunction. Moreover, given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.