Cellular senescence and failure of myelin repair in MS

Mechanisms of Ageing and Development

Koutsoudaki PN, Papadopoulos D, Passias PG, Koutsoudaki P, Gorgoulis VG. Cellular senescence and failure of myelin repair in multiple sclerosis. Mech Ageing Dev. 2020 Dec;192:111366. doi: 10.1016/j.mad.2020.111366. Epub 2020 Sep 28. PMID: 32991921.

This review examined the role of cellular senescence and remyelination failure in MS. OPCs are responsible for the myelination of neurons in the brain when they differentiate into oligodendrocytes in response to microglial signalling. Senescent microglia show dysfunctional degradation which inhibits OPC differentiation into oligodendrocytes. OPC senescence is associated with ageing and exposure to amyloid-beta oligomers, with expression of p16, p21 and senescence-associated beta galactosidase. Some SASP components secreted by senescent cells could interfere with myelination. Senescence also affects other cells like astrocytes, microglia and neurons. Treating senescent astrocytes with rapamycin restored astrocyte ability to support OPC differentiation. Senescence in the BBB increases its permeability and the entry of fibrinogen can interfere with the differentiation of OPCs and affect remyelination. Treatments with senolytics reduced neuroinflammation and cognitive deficits which shows that senescence could contribute to the state of neuroinflammation and to the loss of cognitive function.

Myelin is negatively related to age and loss of myelin could contribute to AD pathology. A number of cell types have been shown to become senescent on exposure to amyloid or tau in AD brains and other papers have shown that myelin disruption is found in AD and could be an early feature. TREM2 which is an AD associated gene is involved in myelin debris removal. When the myelin debris overwhelms microglia, they can become senescent and myelination an be affected.