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

Sagar Gaikwad, Nicha Puangmalai, Alice Bittar, Mauro Montalbano, Stephanie Garcia, Salome McAllen, Nemil Bhatt, Minal Sonawane, Urmi Sengupta, Rakez Kayed

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number109419
JournalCell Reports
Volume36
Issue number3
DOIs
StatePublished - Jul 20 2021

Keywords

  • HMGB1
  • SASP
  • aging
  • astrocytes
  • cognitive functions
  • neurodegeneration
  • neuroinflammation
  • senescence
  • tau oligomers
  • tauopathies

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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