HMGB1‐Mediated Senescence and Brain Inflammation Contributes to Cognitive Dysfunctions

Abstract

AbstractBackgroundHigh mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein, which is excessively released by glial cells during aging and Alzheimer’s Disease (AD). The extracellular HMGB1 serves as a key initiator of neuroinflammation, which is linked to exacerbated cognitive impairments in AD. Importantly, aging ‐ the strongest risk factor for AD is characterized by a chronic, low‐grade inflammation known as inflammaging. Evidence suggests that senescent cells (SC) accumulate with aging and are characterized by an apoptosis‐resistant, arrested cell cycle with a distinct “inflammatory” phenotype also known as senescence‐associated secretory phenotype (SASP). However, the precise etiology of inflammaging in tauopathies remain largely unknown.MethodWe used brain tissues from AD patients and hTau mouse model and performed immunoflourescence, microscopy, astrocyte cell cultures, pharmacological inhibition of HMGB1 in vitro and in vivo in a hTau mouse model to examine role of HMGB1 in senescence, brain inflammation and cognitive dysfunctions. We scored cellular senescence, inflammation, tau pathology (phospho‐tau, tau oligomers, neurofibrillary tangles), Synaptic and postsynaptic proteins, and cognitive functions (Y‐maze and novel‐objective recognition tests).ResultIn this study, we demonstrate that (1) HMGB1 release is linked to advanced age in hTau tauopathy mice. (2) HMGB1 release is a hallmark of senescent cells both in mice and humans. (3) Astrocytes display a senescence‐like phenotype in the brains of patients with AD. (4) Pathological tau oligomers (TauOs) exposure triggers astrocyte senescence through HMGB1 release, which mediates paracrine senescence in adjacent cells and potentiates inflammatory SASP. (5) Inhibition of HMGB1 release using ethyl pyruvate (EP) and glycyrrhizic acid (GA) results in decreased astrocyte senescence and neuroinflammation. (6) Importantly, despite the developed tauopathy and cognitive deficits in 12‐month‐old hTau mice, EP+GA treatment significantly decreased SCs loads in the brain, reduces inflammaging, and thus ameliorated cognitive deficits. Collectively, our data suggest that HMGB1 release promotes inflammaging, and cellular senescence, which could represent an important pathomechanism in the progression of aging‐related diseases, including AD. Future studies are warranted to develop safe and effective therapeutic strategies to control inflammaging and enhance healthy lifespan in patients with tauopathy.ConclusionThe data suggests that HMGB1 release is a key pathomechanism in AD.