Considerations of the role of dysfunction of oligodendrocytes and their precursor cell population in aging usually focus on myelination. Oligodendrocytes are responsible for maintaining the insulating myelin structure that wraps the axons that connect neurons, and which is required for effective propagation of nerve impulses. Researchers have shown that this function declines with age, perhaps to a meaningful degree. Here, however, researchers instead focus on the effects of cellular senescence in oligodendrocyte precursor cells. Senescent cells accumulate with age in the body and brain, and are well known to cause harm to the degree to which they linger and their population grows. Different cell types likely produce different specific harms when they become senescent, however. The researchers show that specific components of the inflammatory signaling produced by senescent oligodendrocyte precursor cells interfere in the activity of other cells in the brain to accelerate cognitive decline.
Aging contributes to cognitive decline in the adult brain with unclear mechanisms. Cellular senescence is characterized by an irreversible cell cycle arrest and featured by the senescence-associated secretory phenotype (SASP). The latter contains pro-inflammatory cytokines, chemokines, growth factors, and proteases, through which senescent cells affect themselves and the neighboring cells via autocrine and paracrine mechanisms. Distinct types of neural cells such as neurons, astrocytes, microglia, and oligodendrocyte precursor cells (OPCs) have been shown to express senescent markers, and these senescent cells accumulate in the brains with aging and neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The selective elimination of these senescent cells attenuates cognitive deficits in naturally aged mice and reduces the accumulation of hyperphosphorylation of tau and amyloid-β in AD transgenic mice. However, despite these beneficial effects, which types of cells are predominant players in driving brain aging and how these senescent cells contribute to aging-related cognitive decline remain unknown.
OPCs, evenly distributed throughout the adult brain, are the primary proliferative cells in the adult central nervous system (CNS). One of the pivotal roles of OPCs is their capability to generate oligodendrocytes (OLs), which produce myelin, ensuring the fast and reliable conduction of action potentials (APs) and providing metabolic support to axons. Apart from being the cellular source of myelin, recent studies point out a myelination-independent function of OPCs in maintaining adult brain networks. OPCs regulate cognitive behaviors via secreting soluble factors and phagocytotic remodeling of synapses and axons. It is worth noting that OPCs form bona fide synapses with glutamatergic and GABAergic neurons. However, it remains unknown how OPCs regulate neuronal plasticity and whether the myelination-independent functions of OPCs are involved in aging-associated cognitive decline.
In this study, we report a myelination-independent role of OPCs in exaggerating cognitive decline in the aging brain via suppressing neuronal plasticity. Our results demonstrate that macroautophagic flux declines in aged OPCs. Inactivation of autophagy promotes the senescence of OPCs, which activates CCL3/CCL5 signaling to activate the CCR5 receptor. Through this, autophagy-defective OPCs impair glutamatergic transmission, neuronal excitability, and long-term potentiation, exaggerating the cognitive decline in the aging brain. Inhibition of CCR5 rescues this impaired neuronal plasticity and cognitive deficits.
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