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

• DOI: 10.2139/ssrn.3753798
• Publication Date: 2021-01-07T08:25:13Z
• Authors: Sagar Gaikwad; Nicha Puangmalai; Alice Bittar; Mauro Montalbano; Stephanie Garcia; Salome McAllen; Nemil Bhatt; Urmi Sengupta; Rakez Kayed
• Keywords: Neuropathology; Oligomer; Senescence

Aging, pathological tau oligomers (TauO) and chronic inflammation in the brain play a central role tauopathies, including Alzheimer's disease (AD) frontotemporal dementia (FTD). However, underlying mechanism of TauO-induced aging-related neuroinflammation remains unclear. We here show that TauO-associated astrocytes display senescence-like phenotype brains AD FTD patients. TauO exposure triggers astrocyte senescence through HMGB1 release inflammatory senescence-associated secretory (SASP), which mediate paracrine adjacent cells. inhibition using ethyl pyruvate (EP) glycyrrhizic acid (GA) prevented p38-MAPK NF-κB– essential signaling pathways for SASP development. Despite developed tauopathy 12-month-old hTau mice, EP+GA treatment significantly decreased senescent cell loads brain, reduced neuroinflammation, thus ameliorated cognitive functions. Collectively, promotes cellular neuropathology, could represent an important common pathomechanism tauopathies FTD.