Tau Oligomer Induced HMGB1 Release Contributes to Cellular Senescence and Neuropathology Linked to Alzheimer's Disease and Frontotemporal Dementia

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.