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

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.

SUBMITTER: Gaikwad S

PROVIDER: S-EPMC8341760 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Gaikwad Sagar S Puangmalai Nicha N Bittar Alice A Montalbano Mauro M Garcia Stephanie S McAllen Salome S Bhatt Nemil N Sonawane Minal M Sengupta Urmi U Kayed Rakez R

Cell reports 20210701 3

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) rele ...[more]

PMID: 34289368

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Dataset Information

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

Publications

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

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