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

Cell Rep. 2021 Jul 20;36(3):109419. 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.

Keywords: HMGB1; SASP; aging; astrocytes; cognitive functions; neurodegeneration; neuroinflammation; senescence; tau oligomers; tauopathies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Animals
  • 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
  • Frontotemporal Dementia / metabolism*
  • Frontotemporal Dementia / pathology*
  • Glycyrrhizic Acid / pharmacology
  • HMGB1 Protein / metabolism*
  • Humans
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phenotype
  • Protein Transport / drug effects
  • Pyruvates / pharmacology
  • tau Proteins / metabolism*


  • HMGB1 Protein
  • Pyruvates
  • tau Proteins
  • ethyl pyruvate
  • Glycyrrhizic Acid