Tau Oligomer Induced HMGB1 Release Contributes to Cellular Senescence and Neuropathology Linked to Alzheimer's Disease and Frontotemporal Dementia
2020
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. We here show that TauO-associated astrocytes display a senescence-like phenotype in the brains of AD and FTD patients. TauO exposure triggers astrocyte senescence through HMGB1 release and inflammatory senescence-associated secretory phenotype (SASP), which mediate paracrine senescence in adjacent cells. HMGB1 release inhibition using ethyl pyruvate (EP) and glycyrrhizic acid (GA) prevented TauO-induced senescence through inhibition of p38-MAPK and NF-κB– the essential signaling pathways for SASP development. Despite the developed tauopathy in 12-month-old hTau mice, EP+GA treatment significantly decreased TauO and senescent cell loads in the brain, reduced neuroinflammation, and thus ameliorated 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.
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