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Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Misra Sen J, Gorospe M, Mattson MP. 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. Epub 2019 Apr 1 PubMed.
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UT Health San Antonio/South Texas VA
It is exciting to see continued interest surrounding cellular senescence in neurodegenerative diseases. Prior studies have reported senescent cells in postmortem human brains from patients with Alzheimer’s disease (Bhat et al., 2012; Musi et al., 2018), Parkinson’s disease (Chinta et al., 2018), and progressive supranuclear palsy (Musi et al., 2018). Mechanistically, tau accumulation induces cellular senescence in neurons (Musi et al., 2018), and microglia (Bussian et al., 2018). Zhang et al. now report that extracellular Aβ induces oligodendrocyte precursor cell (OPC) cellular senescence in Alzheimer’s disease. Their findings provide additional evidence that pathogenic protein accumulation induces cellular senescence in the brain, and that targeting cellular senescence may be an appealing therapeutic approach for clinical studies.
Extracellular Aβ and intracellular tau induce cell-type specific responses (both physiologically and pathogenically), which is highlighted by Zhang et al.’s findings. Their results indicate that in the plaque region, extracellular Aβ induces OPC cellular senescence but causes astrocyte and microglia activation. These results are also consistent with in vitro reports demonstrating OPC senescence in response to abnormal growth conditions/environments (Tang et. al., 2001). Future studies are needed to determine whether OPC cellular senescence is specific to Aβ, or whether other pathogenic protein aggregates (e.g., tau, α-synuclein, TDP-43, etc.) can induce a similar response. In our study we did not observe upregulated senescence-associated gene expression in 3xTgAD mice with high plaque burden without neurofibrillary tangles; however, we did not enrich for regions surrounding the plaques as done by Zhang et al. (Musi et al., 2018). For our analyses, we extracted RNA from whole mouse forebrain. Compared to age-matched controls, this methodology revealed a significant upregulation in senescence-associated gene expression in mice with neurofibrillary tangles, but not in mice with only plaque pathology. Collectively the studies suggest that tau pathology induces a greater senescent burden than Aβ plaque accumulation.
In general, neurodegenerative dementing disease research has not given OPCs and oligodendrocytes the same attention as other cell types. Investigating how the myelinating cells and their precursors respond to protein accumulation will continue to enhance our overall understanding of disease pathogenesis. For example, understanding the functional consequences of senescent OPCs will be an important next step in this line of investigation (i.e., can they migrate, respond to neuronal damage, differentiate, contribute to myelin repair, etc.?).
Zhang et al.’s work indicates that treating young mice with senolytics dasatinib and quercetin (D+Q) prevented Aβ accumulation and OPC senescence. It remains unknown whether the clearance of senescent OPCs without a reduction in Aβ (as shown in the acute nine-day study) is sufficient to improve behavior; or rather a reduction in Aβ is needed for these improvements (as shown with the 11-week treatment strategy). Also, the ability of D+Q to prevent plaque accumulation when given as a prophylactic treatment, prior to Aβ deposition and senescence onset, suggests “non-senolytic effects” of D+Q. Future studies will be needed to differentiate between senolytic and non-senolytic effects of D+Q and other drugs that target senescent cells.
Overall, it is promising to see prophylactic benefits of D+Q in a model of amyloidosis as it extends on our findings showing improvements using the same treatment in advanced neurodegeneration. Collectively our studies indicate that treatment with D+Q may be a useful approach to prevent or delay AD pathogenesis by reducing Aβ plaque accumulation and senescent OPCs as well as stop disease progression in advanced stages by reducing senescent neurofibrillary tangle-containing neurons.
References:
Bhat R, Crowe EP, Bitto A, Moh M, Katsetos CD, Garcia FU, Johnson FB, Trojanowski JQ, Sell C, Torres C. Astrocyte senescence as a component of Alzheimer's disease. PLoS One. 2012;7(9):e45069. PubMed.
Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell. 2018 Dec;17(6):e12840. Epub 2018 Oct 11 PubMed.
Chinta SJ, Woods G, Demaria M, Rane A, Zou Y, McQuade A, Rajagopalan S, Limbad C, Madden DT, Campisi J, Andersen JK. Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson's Disease. Cell Rep. 2018 Jan 23;22(4):930-940. Epub 2018 Jan 28 PubMed.
Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature. 2018 Oct;562(7728):578-582. Epub 2018 Sep 19 PubMed.
Tang DG, Tokumoto YM, Apperly JA, Lloyd AC, Raff MC. Lack of replicative senescence in cultured rat oligodendrocyte precursor cells. Science. 2001 Feb 2;291(5505):868-71. Epub 2001 Jan 18 PubMed.
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