Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's 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 (Arriagada, Growdon, Hedley‐Whyte, & Hyman, 1992), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires‐Jones, Pitstick, Carlson, & Hyman, 2009), which suggests that secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT‐containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Using four AD transgenic mouse models, we found that NFTs, but not Aβ plaques, display a senescence‐like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. 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, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

22 15355 Lambda Drive 23 STCBM 2.100.05 24 San Antonio, TX 78245 25 Phone: (210) 562-6117 26 Tau protein accumulation is the most common pathology among degenerative brain 27 diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), 28 traumatic brain injury (TBI) and over twenty others 1 . Tau-containing neurofibrillary tangle 29 (NFT) accumulation is the closest correlate with cognitive decline and cell loss, yet the 30 mechanisms mediating tau toxicity are poorly understood. NFT-containing neurons do 31 not die, which suggests secondary mechanisms are driving toxicity 2 . We evaluated gene 32 expression patterns of NFT-containing neurons microdissected from AD patient brains 3 33 and found they develop an expression profile consistent with cellular senescence 34 described in dividing cells. This complex stress response induces a near permanent cell 35 cycle arrest, adaptations to maintain survival, cellular remodeling, and metabolic 36 dysfunction 4 . Moreover, senescent cells induce chronic degeneration of surrounding 37 tissue through the secretion of pro-inflammatory, pro-apoptotic molecules termed the 38 senescence-associated secretory phenotype (SASP) 5 . Using transgenic mouse models of 39 tau-associated pathogenesis we found that NFTs induced a senescence-like phenotype 40 including DNA damage, karyomegaly, mitochondrial dysfunction and SASP. Cdkn2a 41 transcript level, a hallmark measure of senescence, directly correlated with brain atrophy 42 and NFT load. This relationship extended to postmortem brain tissue from humans with 43 PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late 44 stage pathology were treated with senolytics to remove senescent cells. Despite the 45 advanced age and disease progression, senolytic treatment reduced total NFT burden, 46 neuron loss and ventricular enlargement; and normalized cerebral blood flow to that of 47 non-transgenic control mice. Collectively, these findings indicate that NFTs induce 48 cellular senescence in the brain, which contributes to neurodegeneration and brain 49 dysfunction. Moreover, given the prevalence of tau protein deposition among 50 neurodegenerative diseases, these findings have broad implications for understanding, 51 and potentially treating, dozens of brain diseases. 52In human AD, tau-containing NFT density closely tracks with disease severity 2 . However, 53NFTs do not induce immediate cell death 6 ; instead in silico modeling predicts that NFT-54 containing neurons may survive decades 7 . To gain insight into how NFT-containing neurons 55 endure an environment that is toxic to histologically adjacent cells 2,6 , we queried the publicly 56 available GEO Profiles database 8 for gene sets specific to NFTs. We evaluated laser capture 57 microdissected cortical neurons containing NFTs from AD brains (GEO accession GDS2795) 58 and compared them to adjacent histopathologically normal neurons for a within-subjects study 59 design 3 . NFT containing neurons upregulated genes involved in cell...