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

Abstract

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.

Oligomeric amyloid beta prevents myelination in a clusterin-dependent manner

“…Intriguingly, Lumican is known to be involved in the recruitment of immune cells and the regulation of cellular infiltration of tissue [71][72][73][74] . This cluster showed significant upregulation of genes related to cytokine mediated signaling, consistent with recent papers indicating that OPCs may be playing an active role in regulating the immune system, interrogating the function and transcriptional signature of this cluster of OPCs may further elucidate how OPCs may be interacting with the immune system and modulating the CNS environment to affect neuronal behavior and function 16,17,20,63 .…”

“…For example, OPC1 expresses high levels of Clusterin, a gene known to be upregulated in both Alzheimer's disease and multiple sclerosis (MS) 61,62 . OPCs have recently been shown to potentially play an active role in the pathology of MS and have been implicated in the progression of Alzheimer's disease 17,20,63 . Given these associations with Alzheimer's disease and MS, and the known role of clusterin in multiple CNS pathologies, interrogating the functions of this cluster of OPCs may be particularly important in revealing novel ways OPCs help maintain homeostasis and how they subsequently may be playing an active role in contributing to or protecting against CNS pathology [63][64][65][66] .…”

NG2 glia are required for maintaining microglia homeostatic state

“…For example, it has been known that microglia associated with Aβ plaques in the AD brain display drastic downregulation of the homeostatic microglia signature genes (Keren‐Shaul et al, ; Krasemann et al, ), which may be accompanied by functional changes that are directly related to disease progression. In contrast, Aβ plaque associated NG2 glia showed a senescent phenotype (Zhang et al, ), indicating the loss of NG2 glia function in the plaque‐containing microenvironment. The results of the current study suggest that the loss of the homeostatic signature in the plaque‐associated microglia might be caused by a locally impaired NG2 glia–microglia interaction.…”

“…NG2 glia are identified by the coexpression of NG2 (also known as chondroitin sulfate proteoglycan 4) and platelet-derived growth factor receptor alpha (PDGFRα), and function as precursor cells for oligodendrocyte during development or myelin damages (Kang, Fukaya, Yang, Rothstein, & Bergles, 2010;Tripathi, Rivers, Young, Jamen, & Richardson, 2010;Trotter, Karram, & Nishiyama, 2010). Interestingly, in contrast to microglia, a recent study found that Aβ plaque associated NG2 glia in the AD brain showed a senescent phenotype (Zhang et al, 2019), suggesting the impaired NG2 glia function in the plaquecontaining microenvironment. Whether the local loss of NG2 glia function contributes to the disturbed homeostatic microglia signature around Aβ plaques or more generally, whether NG2 glia play a role in maintaining microglia homeostatic state in the healthy CNS is unknown.…”

NG2 glia are required for maintaining microglia homeostatic state

“…NG2 glia are identified by the co-expression of NG2 (also known as chondroitin sulfate proteoglycan 4) and platelet-derived growth factor receptor alpha (PDGFR), and function as oligodendrocyte precursor cells during development or myelin damages (Kang et al 2010;Tripathi et al 2010;Trotter et al 2010). Interestingly, in contrast to microglia, a recent study found that Aplaque-associated NG2 glia in the AD brain showed a senescent phenotype (Zhang et al 2019), suggesting the impaired NG2 glia function in the plaque-containing microenvironment. Whether the local loss of NG2 glia function contributes to the disturbed homeostatic microglia signature around Aplaques or more generally, whether NG2 glia play a role in maintaining microglia homeostatic state in the healthy CNS is unknown.…”