Editors' ChoiceAlzheimer’s Disease

Targeting senescence within the Alzheimer’s plaque

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Science Translational Medicine  17 Apr 2019:
Vol. 11, Issue 488, eaax4869
DOI: 10.1126/scitranslmed.aax4869


Amyloid β drives senescence of oligodendrocyte progenitor cells, presenting a potential therapeutic target.

The term “cellular senescence” describes a condition in which cells undergo irreversible cell cycle arrest in response to stress. Senescent cells accumulate in tissues during aging, secreting proinflammatory and matrix-degrading molecules as part of a senescence-associated secretory phenotype (SASP), which is linked to age-related tissue inflammation and disease. Senescence has been described extensively in peripheral tissues and linked with age-related conditions such as osteoarthritis and cancer, whereas elimination of senescent cells provides protection in these conditions. Whether senescence impacts age-related neurodegenerative disease such as Alzheimer’s Disease (AD) is unknown. A hallmark of AD is the formation of amyloid β (Aβ) plaques in the brain, with astrocytes and microglia accumulating in the plaque environment. A third type of glial cells, oligodendrocytes, arise from oligodendrocyte progenitor cells (OPCs). OPCs are mobilized in response to injury and differentiate to oligodendrocytes, which myelinate neurons. However, it is unclear whether OPCs accumulate around plaques and whether this impacts AD disease.

Using a combination of staining and imaging approaches coupled with transgenic mouse experiments, Zhang et al. identified senescent OPCs with a proinflammatory phenotype in the Aβ plaque environment in an AD mouse model and in AD human brains. Futhermore, they discovered that a proportion of OPCs exposed to Aβ in vitro became senescent. The authors did not detect the presence of senescent astrocytes or microglia around the plaques. Dasatinib and quercetin (D + Q) are approved senolytic compounds, which can remove senescent cells. Long-term treatment with D + Q in the amyloid precursor protein and presenelin-1 (APP/PSI) mouse model of AD specifically targeted the senescent OPCs in the plaque environment, improving the animals’ learning and memory, along with reductions in plaque load and proinflammatory cytokine production. These findings reveal a new mechanism of AD pathogenesis, which can be targeted by compounds currently under investigation for other age-related diseases. Given that no disease-modifying agents exist for AD, these findings may represent an important step in AD translational medicine.

Another feature of AD is the accumulation of hyperphosphorylated tau tangles (pTau), and other groups had already identified astrocyte and microglia senescence in a mouse model with pTau. Therefore, it remains to be determined whether astrocytes and microglia may also undergo senescence in human AD, where both pTau and Aβ plaques coexist. Nonetheless, these studies pave the way for future experimentation with senolytic therapies in AD and other age-related neuropathologies.

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