Tau protein aggregation is associated with cellular senescence in the brain

Abstract

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.

Targeting senescent cells alleviates obesity‐induced metabolic dysfunction

“…Cellular senescence is a cell fate that entails proliferative arrest and acquisition of a pro‐inflammatory senescence‐associated secretory phenotype (SASP; Coppe et al, ). Although senescent cells exist in relatively small numbers in any particular tissue, they have been associated with multiple diseases of aging and are emerging as useful therapeutic targets for age‐related diseases, including cardiovascular disease, pulmonary fibrosis, neurodegeneration, and osteoporosis (Farr et al, ; Musi et al, ; Roos et al, ; Schafer et al, ). A number of stimuli, including potentially oncogenic, inflammatory, damage‐related, and metabolic stimuli, can trigger a senescence response (Munoz‐Espin & Serrano, ).…”

“…(b) On the other hand, Q, unlike D, is effective against senescent endothelial cells (Zhu et al, ), a cell type implicated in vascular complications of diabetes (Caballero, ). (c) D + Q is effective in alleviating multiple age‐ and senescence‐associated disorders, including many that are frequent complications or comorbidities of diabetes in preclinical animal models; these comorbidities include arteriosclerosis, vascular hyporeactivity, osteoporosis, hepatic steatosis, physical dysfunction, neurodegeneration, and neuropsychiatric dysfunction (Farr et al, ; Kirkland & Tchkonia, ; Kirkland et al, ; Musi et al, ; Ogrodnik et al, ,; Roos et al, ; Xu et al, ). (d) Navitoclax and other BCL‐2 family member inhibitors can be toxic, for example, causing severe thrombocytopenia, which can occur even with intermittent dosing (Wilson et al, ).…”

The Danger of Being Too Sympathetic: Norepinephrine in Alzheimer's Disease and Graying of Hair

“…Decoupling beta-amyloid deposition from hyperphosphorylated tau formation could be of great significance. This needs to be tempered by the complicated phenotype of AD, which may involve prion-like tau [32][33][34] or tau-induced cell senescence 35 among other mechanisms. Once prion-like tau is formed, or senescence is induced, it may take more than blocking an amyloid-tau positive feedback to stop progression.…”

Cell Senescence, Telomerase, and Senolytic Therapy

“…1) Genetically altered animals may not adequately represent the pathology found in aging human patients [16,53]. Such models frequently genetically-modify an animal (for example, to increase tau tangle production) then show that senolytics may ameliorate the artificially elevated bio-marker.…”