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Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model
Open accessAbstract
Neuritic plaques, a pathological hallmark in Alzheimer's disease (AD) brains, comprise extracellular aggregates of amyloid-beta (Aβ) peptide and degenerating neurites that accumulate autolysosomes. We found that, in the brains of patients with AD and in AD mouse models, Aβ plaque-associated Olig2- and NG2-expressing oligodendrocyte progenitor cells (OPCs), but not astrocytes, microglia, or oligodendrocytes, exhibit a senescence-like phenotype characterized by the upregulation of p21/CDKN1A, p16/INK4/CDKN2A proteins, and senescence-associated β-galactosidase activity. Molecular interrogation of the Aβ plaque environment revealed elevated levels of transcripts encoding proteins involved in OPC function, replicative senescence, and inflammation. Direct exposure of cultured OPCs to aggregating Aβ triggered cell senescence. Senolytic treatment of AD mice selectively removed senescent cells from the plaque environment, reduced neuroinflammation, lessened Aβ load, and ameliorated cognitive deficits. Our findings suggest a role for Aβ-induced OPC cell senescence in neuroinflammation and cognitive deficits in AD, and a potential therapeutic benefit of senolytic treatments.
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“In preclinical studies, co-administration of Dasatinib and Quercetin (DQ) improved aspects related to physical function (e.g., endurance and speed) and cognition (e.g., reduced neurofibrillary tangle density/neuron loss).7,15,24”
From A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease (2025) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Importantly, clearance of Sncs either genetically or pharmacologically in mice leads to functional improvements in models of neurodegenerative diseases such as PD and AD (57–59).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [59]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Senescence has been observed in neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells (57–59).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [59]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“These two mouse models have greatly accelerated our understanding of whether senescent cells contribute to ageing and age-related diseases, at least in model organisms, for numerous diseases, including Parkinson disease196, Alzheimer disease197,198, atherosclerosis175, idiopathic pulmonary fibrosis199, chronic obstructive pulmonary disease200 and osteoarthritis201.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [198]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Senescent astrocytes and microglia accumulate in a tau‐dependent mouse model of AD where they contribute to cognitive decline in these mice (Bussian et al, 2018; Zhang et al, 2019).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Zhang et al, 2019
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“Previous studies have highlighted senescence in multiple brain cell types in AD [3, 16, 32, 52, 80].”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [80]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This therapeutic approach, referred to as senolytic, improves healthy lifespan in various laboratory model systems, including ADRD transgenic mice [2,4,7].”
From Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease (2025) · cites this paper as [4]
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“Recent evidence suggests that the accumulation of senescent cells, which can release a variety of pro-inflammatory, apoptotic, and toxic by-products, called the senescence-associated secretory phenotype (SASP), is one of the drivers of deficits in both cognition11, 12, 13, 14, 15, 16 and mobility.7,17, 18, 19, 20, 21, 22”
From A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease (2025) · cites this paper as [15]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“treatment of an Alzheimer’s disease mouse model with a senolytic agent improved memory and learning ability160”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [160]
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In the citing paper
“Given the compelling evidence provided by preclinical research6,19, coupled with the encouraging safety profiles reported in human studies of D + Q for other disease indications27,28, we conducted the first clinical trial of senolytic therapy for AD.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [19]
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In the citing paper
“Other research teams confirmed the association between tau and senescence in PS19 tau transgenic mice8 and the effective clearance of senescent cells using D + Q in the Tg(APP/PS1) Aβ-producing mouse model19.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [19]
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In the citing paper
“While we identified Olig2+ cells expressing some senescence markers, joint use of transcriptomic data was able to more probably ascribe this senescence signature predominantly to oligodendrocytes rather than OPC, which had been implicated in an earlier preclinical study [80].”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [80]
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“Preclinical studies using different models have suggested that senolytic treatments can reduce the abundance of senescent cells, disease-relevant pathology and cognitive deficits [8, 56, 80].”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [80]
The cited source says what the claim attributes to it.
In the citing paper
“the pharmacological and genetic elimination of senescent cells has shown therapeutic benefits for AD pathology in mouse models of tau and amyloid pathology [11, 83, 122].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [122]
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In the citing paper
“D + Q has demonstrated successful reduction in senescent cell burden, inflammatory SASP, AD-related neuropathological burden of tau-containing neurofibrillary tangles (NFTs) [2] and Aβ plaques [4], and age-associated cognitive deficits [8,9].”
From Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease (2025) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer’s disease (AD).”
From Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease (2025) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“An independent preclinical trial also reported downregulation of IL1β in the brain in response to D + Q [4].”
From Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease (2025) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“A key contributor to the development and progression of inflammaging is the senescence associated secretory phenotype (SASP) – a damaging byproduct of senescent cells [63], and a potential driver of Alzheimer’s pathogenesis [64].”
In the citing paper
“These oligodendrocyte signatures are distinct from those recently associated with multiple sclerosis21 and senescence43.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [43]
In the citing paper
“The delivery of senolytics in AD mice reduces the Aβ load and the levels of proinflammatory factors, thereby enhancing cognitive funciton.430”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [430]
In the citing paper
“Emerging evidence suggests a detrimental impact of senescent cells, including p16INK4A-positive senescent astrocytes and microglia, and Aβ plaque-associated Olig2- and NG2-expressing p16INK4A-positive oligodendrocyte progenitor cells (OPCs) in neuronal loss and cognitive impairment in mouse models of AD (Bussian et al., 2018; Zhang et al., 2019).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Zhang et al., 2019
In the citing paper
“Senolytic elimination of Aβ-associated senescent OPCs or Tau pathology-associated senescent glial cells ameliorates cognitive impairment in different AD mouse models (Bussian et al., 2018; Zhang et al., 2019).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Zhang et al., 2019
In the citing paper
“The involvement of senescence and SASP in MCI and AD is further strengthened by experimental evidence that senolytic therapy provides beneficial effects in accelerated aging, 106 tauopathy, 22 and AD mouse models 25 by reducing brain inflammation.”
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 [25]
In the citing paper
“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 [25]
In the citing paper
“eliminating senescent cells with senolytics reduces tau aggregation and inflammation and improves cognitive performance in vivo.”
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 [25]
In the citing paper
“Several studies demonstrated that tau aggregates can trigger cellular senescence and inflammation”
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 [25]
In the citing paper
“The burden of senescent cells in the brain increases with advanced chronological age and neurodegenerative diseases, and occurs across cell types including neurons, microglia, astrocytes, oligodendrocyte precursor cells, and endothelial cells (28–32).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [30]
In the citing paper
“An independent study conducted by Zhang et al. validated the finding of D+Q clearance of senescent cells in the brain of an β-amyloid model of AD pathology (30).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [30]
In the citing paper
“To date, research conducted across six transgenic AD mouse models has demonstrated that orally administered senolytic drugs ablate senescent cells in the brain and alleviate AD-relevant pathogenesis (28–30, 32).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [30]
In the citing paper
“This drug combination eliminates the senescent cells (also known as “senolytic therapy”), reduces tau pathology, amyloid load, and neuroinflammation, and ameliorates cognitive impairment in preclinical studies [256, 257].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [256]
In the citing paper
“CD38 is emerging as a key enzyme involved in inflammageing and senescence45,105,106, which are strongly associated with neurodegenerative diseases124,128,168,169.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [169]
In the citing paper
“Successful repurposing in AD is supported by in vivo studies in amyloid precursor protein (APP)/PS1 mutant transgenic mouse models.The combination seems to act by the selective removal of senescent cells from the Aβ plaque environment, leading to a reduction of proinflammatory cytokine secretion and a decrease of Aβ concentration, with an overall amelioration of cognitive disturbances.66”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [66]
In the citing paper
“Senotherapy has been shown to ameliorate phenotypes in all of these mouse models, attenuating tau phosphorylation and aggregation, 39 reducing neuroinflammation and amyloid β plague load, and improving cognitive deficits.40”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [40]
In the citing paper
“Zhang et al. employed a senolytic cocktail of dasatinib plus quercetin (D + Q) to validate that senescent OLIG2- and NG2-expressing oligodendrocyte progenitor cells (OPCs) contribute to cognitive impairment in an AD mouse model [56].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [56]
In the citing paper
“More recently, researchers have identified senescent‐like brain cells in murine models of AD and tauopathy, and their removal via senolytic drugs seems to mitigate pathology and improve cognition (Bussian et al, 2018; Musi et al, 2018; Zhang et al, 2019; Ogrodnik et al, 2021).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Zhang et al, 2019
In the citing paper
“Senescent‐like phenotypes have also been identified in oligodendrocyte precursor cells (OPCs) in APP/PS1 mice, and their removal has been shown to mitigate amyloid load and cognitive decline (Zhang et al, 2019).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Zhang et al, 2019
In the citing paper
“It has since been shown that removal of senescent cells in the brain mitigates neurofibrillary tangle (NFT) burden, amyloid burden, neuronal loss, and cognitive decline in mouse models of tauopathy (Bussian et al, 2018; Musi et al, 2018), AD (Zhang et al, 2019), PD (Chinta et al, 2018), and normal aging (Ogrodnik et al, 2021).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Zhang et al, 2019
In the citing paper
“Putative senescent states have been suggested in a variety of neural subpopulations with aging and in various disease contexts, including microglia [26–30], neurons [31–33], astrocytes [26,34,35], and oligodendrocyte progenitor cells [36].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [36]
In the citing paper
“Regardless of the hypothesized identity of the senescent population, each of these studies demonstrated pathology mitigation following pharmacological removal of senescent cells [26,33,36].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [36]
In the citing paper
“Recent studies have produced evidence for senescence in neurons and oligodendrocyte progenitors in other mouse models of tauopathy and AD [33,36].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [36]
In the citing paper
“Nevertheless, some senolytics have been effectively used in mouse models of neurological disease to alleviate pathology including dasatinib and quercetin [36] and navitoclax [26], which has led to senolytic therapies entering clinical trials for the modulation of AD [171].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [36]
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Metadata
- Authors
- Zhang, P., Kishimoto, Y., Grammatikakis, I., Gottimukkala, K., Cutler, R. G., Zhang, S., Abdelmohsen, K., Bohr, V. A., Misra Sen, J., Gorospe, M., & Mattson, M. P.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Zhang, Peisu
- Mattson, Mark P.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2019-04-01
- Volume
- 22
- Issue
- 5
- Pages
- 719-728
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6605052
- OpenAlex
- W2928157366
- Cited by
- 977
- References
- 48
- Citations by year
- 2026: 109 · 2025: 157 · 2024: 168 · 2023: 135 · 2022: 133 · 2021: 131 · 2020: 118 · 2019: 26
- FWCI
- 69.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 AG999999)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- senolytic therapy, Alzheimer's disease, amyloid-beta, oligodendrocyte precursor cells, cellular senescence, neuroinflammation, cognitive impairment, senescent cell clearance, Olig2, NG2, replicative senescence, senescence-associated β-galactosidase, CDKN1A/p21, CDKN2A/p16, amyloid plaques
- MeSH terms
- Dasatinib, Oligodendrocyte Precursor Cells, Alzheimer Disease, Animals, Disease Models, Animal, Female, Male, Mice, Transgenic, Quercetin, Amyloid beta-Peptides, Prosencephalon, Cellular Senescence, Maze Learning, Plaque, Amyloid
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