Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia
Open accessAbstract
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.
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Ast-AD revealed fewer GFAP-positive cells than S100B-positive ones, with low HMGB1 and IL-10 and elevated IL-6 and C/EBPα gene levels.
“Ast-AD revealed fewer GFAP-positive cells than S100B-positive ones, with low HMGB1 and IL-10 and elevated IL-6 and C/EBPα gene levels, already pointing to some altered properties [27,72,120].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [120]
The Results describe GFAP-positive astrocytes in AD and FTD brain tissue and increased HMGB1 and IL-6 in TauO-associated or TauO-stimulated astrocytes. Our copy does not report findings for Ast-AD, compare GFAP-positive with S100B-positive cell counts, or give the claimed IL-10 and C/EBPα gene levels (searched: Ast-AD, S100B, IL-10, C/EBPα). (LLM, conf=0.76)
Experimental — accuracy not yet measuredExposure to pathological protein aggregates such as amyloid beta and TauO triggers HMGB1 release, chronic inflammation, and upregulation of RAGE and TLR4 signaling pathways.
“exposure to pathological protein aggregates such as Aβ and TauO triggers HMGB1 release, chronic inflammation, and upregulation of RAGE and TLR4 signaling pathways. 57”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [57]
Extracellular HMGB1 promotes paracrine senescence in neighboring cells and induces chronic tissue inflammation via the SASP.
“we and others demonstrated that extracellular HMGB1 promotes paracrine senescence in neighboring cells and induces chronic tissue inflammation via the SASP, 56 , 57”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [57]
In postmortem brain tissue from Alzheimer's disease patients, translocation of HMGB1 from the nucleus to the cytoplasm is a molecular signature of senescence and brain inflammation.
“We reported that in postmortem brain tissue from AD patients, translocation of HMGB1 from the nucleus to the cytoplasm is a molecular signature of senescence and brain inflammation. 57”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [57]
Senolytic therapy has shown promising results in various animal models, including tauopathies.
“Senolytic therapy has shown promising results in various animal models, including tauopathies.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [57]
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Relationship among α‑synuclein, aging and inflammation in Parkinson's disease (Review)
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<scp>ApoE4</scp> expression disrupts tau uptake, trafficking, and clearance in astrocytes
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Mechanisms involved in the HMGB1 modulation of tumor multidrug resistance (Review)
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Targeting secretory autophagy in solid cancers: mechanisms, immune regulation and clinical insights
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What have we learned from past failures of investigational drugs for Alzheimer’s disease?
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The Role of Senescence-Associated Secretory Phenotype in Bone Loss
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Defining and characterizing neuronal senescence, ‘neurescence’, as GX arrested cells
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Senescent cells in the brain and where to find them
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Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease
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Tau proteins and senescent Cells: Targeting aging pathways in Alzheimer’s disease
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Post-translational modifications in sepsis-induced organ dysfunction: mechanisms and implications
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DAMP signaling networks: from receptors to diverse pathophysiological functions
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Alzheimer's Disease and Aging Association: Identification and Validation of Related Genes
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The effects of cGAS-STING inhibition in liver disease, kidney disease, and cellular senescence
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Positron Emission Tomography in Animal Models of Tauopathies
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- Authors
- Gaikwad, S., Puangmalai, N., Bittar, A., Montalbano, M., Garcia, S., McAllen, S., Bhatt, N., Sonawane, M., Sengupta, U., & Kayed, R.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Kayed, Rakez
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 36
- Issue
- 3
- Pages
- 109419
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC8341760
- OpenAlex
- W3186179545
- Cited by
- 234
- References
- 109
- Citations by year
- 2026: 49 · 2025: 55 · 2024: 52 · 2023: 43 · 2022: 28 · 2021: 6
- FWCI
- 20.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (R01AG054025, R01AG060718, R01NS094557, RFA1AG055771)
- American Heart Association (17CSA33620007)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- tau oligomers, HMGB1 release, cellular senescence, astrocytes, senescence-associated secretory phenotype, neuroinflammation, Alzheimer's disease, frontotemporal dementia, tauopathy, p38 MAPK, NF-κB, ethyl pyruvate, glycyrrhizin, paracrine senescence, cognitive function
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Brain, Cell Nucleus, Cells, Cultured, Cognition Disorders, Humans, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Pyruvates, tau Proteins, Cellular Senescence, Glycyrrhizic Acid, Protein Transport, HMGB1 Protein, Mice, Frontotemporal Dementia
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