Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia

• Published in: Cell reports (Cambridge) 2021-07, Vol.36 (3), p.109419-109419, Article 109419
• Main Authors: Gaikwad, Sagar, Puangmalai, Nicha, Bittar, Alice, Montalbano, Mauro, Garcia, Stephanie, McAllen, Salome, Bhatt, Nemil, Sonawane, Minal, Sengupta, Urmi, Kayed, Rakez
• Format: Article
• Language: English
• Subjects: aging; Alzheimer Disease - complications; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Animals; astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Brain - drug effects; Brain - pathology; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cells, Cultured; Cellular Senescence - drug effects; Cognition Disorders - complications; Cognition Disorders - pathology; cognitive functions; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; Glycyrrhizic Acid - pharmacology; HMGB1; HMGB1 Protein - metabolism; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; neurodegeneration; neuroinflammation; Phenotype; Protein Transport - drug effects; Pyruvates - pharmacology; SASP; senescence; tau oligomers; tau Proteins - metabolism; tauopathies
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109419

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 κB (NF-κB)—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. [Display omitted] •Postmortem AD and FTD brain tissues exhibit TauO-associated senescent astrocytes•Direct exposure of TauO triggers cellular senescence in cultured astrocytes•HMGB1 release is a crucial event during TauO-induced cellular senescence•HMGB1 released by senescent cells may contribute to the progression of tauopathies Gaikwad et al. demonstrate that TauO-associated astrocytes exhibit senescence-like phenotype in the brain of patients with AD and FTD. They find that HMGB1 release is a crucial event for TauO-induced cellular senescence, tauopathy progression, and cognitive deficits, indicating that HMGB1 release could represent an important common pathomechanism in tauopathies.