| First Author | Gaikwad S | Year | 2021 |
| Journal | Cell Rep | Volume | 36 |
| Issue | 3 | Pages | 109419 |
| PubMed ID | 34289368 | Mgi Jnum | J:334263 |
| Mgi Id | MGI:6876902 | Doi | 10.1016/j.celrep.2021.109419 |
| Citation | Gaikwad S, et al. (2021) Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer's disease and frontotemporal dementia. Cell Rep 36(3):109419 |
| abstractText | Aging, pathological tau oligomers (TauO), and chronic inflammation in the brain play a central role in tauopathies, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, the underlying mechanism of TauO-induced aging-related neuroinflammation remains unclear. Here, we show that TauO-associated astrocytes display a senescence-like phenotype in the brains of patients with AD and FTD. TauO exposure triggers astrocyte senescence through high mobility group box 1 (HMGB1) release and inflammatory senescence-associated secretory phenotype (SASP), which mediates paracrine senescence in adjacent cells. HMGB1 release inhibition using ethyl pyruvate (EP) and glycyrrhizic acid (GA) prevents TauO-induced senescence through inhibition of p38-mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB)-the essential signaling pathways for SASP development. Despite the developed tauopathy in 12-month-old hTau mice, EP+GA treatment significantly decreases TauO and senescent cell loads in the brain, reduces neuroinflammation, and thus ameliorates cognitive functions. Collectively, TauO-induced HMGB1 release promotes cellular senescence and neuropathology, which could represent an important common pathomechanism in tauopathies including AD and FTD. |
