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Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model.


Maximus Peto’s Commentary

The findings of this research group (in mouse experiments) suggest that Abeta aggregates can induce senescence in oligodendrocyte progenitor cells, and senolytic treatments seemed to have multiple benefits in this model.


Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model.
Nat Neurosci. 2019 May;22(5):719-728.
Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Misra Sen J, Gorospe M, Mattson MP
DOI: 10.1038/s41593-019-0372-9
PubMed publication date (edat): 4/3/2019

Abstract

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.
Comment in
* Senescent glia spell trouble in Alzheimer’s disease. [Nat Neurosci. 2019]

PMID: 30936558
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605052/

Maximus Peto

Max Peto is a longevity researcher and founder of Long Life Labs. A biochemist by training, he studies the biochemistry of aging and longevity and has worked with research organizations such as SENS Research Foundation, Methuselah Foundation, BioAge Labs, Life Extension Foundation, and Ichor Therapeutics. His work at Long Life Labs is focused on empowering people to understand and manage the most critical factors for better health and longer life.

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