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

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 Oli...

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Published in:	Nature neuroscience Vol. 22; no. 5; pp. 719 - 728
Main Authors:	Zhang, Peisu, Kishimoto, Yuki, Grammatikakis, Ioannis, Gottimukkala, Kamalvishnu, Cutler, Roy G, Zhang, Shiliang, Abdelmohsen, Kotb, Bohr, Vilhelm A, Misra Sen, Jyoti, Gorospe, Myriam, Mattson, Mark P
Format:	Journal Article
Language:	English
Published:	United States Nature Publishing Group 01.05.2019
Subjects:	Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Alzheimer Disease - psychology Alzheimer's disease Amyloid beta-Peptides - administration & dosage Amyloid beta-Peptides - metabolism Animal models Animals Astrocytes Axons Cells (biology) Cellular Senescence - drug effects Cognitive ability Cyclin-dependent kinase inhibitors Dasatinib - administration & dosage Disease Models, Animal Female Galactosidase Glial stem cells Inflammation INK4 protein Interrogation Male Maze Learning - drug effects Mice, Transgenic Microglia Olig2 protein Oligodendrocyte Precursor Cells - metabolism Oligodendrocytes Phenotypes Plaque, Amyloid - ultrastructure Progenitor cells Prosencephalon - metabolism Prosencephalon - ultrastructure Proteins Quercetin - administration & dosage Senescence Senile plaques β-Amyloid β-Galactosidase
ISSN:	1097-6256, 1546-1726, 1546-1726
Online Access:	Get full text
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1097-6256 1546-1726 1546-1726
DOI:	10.1038/s41593-019-0372-9