The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis

Abstract

In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The clearance of myelin debris (phagocytosis) from the site of demyelination by microglia is critically important to achieve adequate remyelination and to slow the progression of the disease. However, how microglia phagocytose the myelin debris, and why clearance is impaired in MS, is not fully known; likewise, the role of the microglia in remyelination remains unclear. Recent studies using cuprizone (CPZ) as an animal model of central nervous system demyelination revealed that the up‐regulation of signaling proteins in microglia facilitates effective phagocytosis of myelin debris. Moreover, during demyelination, protective mediators are released from activated microglia, resulting in the acceleration of remyelination in the CPZ model. In contrast, inadequate microglial activation or recruitment to the site of demyelination, and the production of toxic mediators, impairs remyelination resulting in progressive demyelination. In addition to the microglia‐mediated phagocytosis, astrocytes play an important role in the phagocytic process by recruiting microglia to the site of demyelination and producing regenerative mediators. The current review is an update of these emerging findings from the CPZ animal model, discussing the roles of microglia and astrocytes in phagocytosis and myelination.

Histological and Top-Down Proteomic Analyses of the Visual Pathway in the Cuprizone Demyelination Model

“…In this model, animals are fed CPZ, which is preferentially toxic to mature oligodendrocytes, inducing oligodendrocytosis (i.e. loss or degeneration of oligodendrocytes) and subsequent demyelination, as well as micro- and astro-glial activation (Almuslehi et al 2020 ; Sen et al 2019a , 2020b , 2022 ). The mechanisms underlying oligodendrocytosis induced by CPZ are still poorly understood.…”

“…It has been proposed that the metal (e.g. copper) chelating properties of CPZ disrupt metabolic processes in oligodendrocytes due to the inhibition of mitochondrial enzymes (reviewed in Sen et al 2019b , 2022 ). However, very little is known about the actions of CPZ on the visual pathway, and much of what is reported is contradictory (reviewed in Sen et al 2019b ).…”

The Extracellular Matrix Proteins Tenascin-C and Tenascin-R Retard Oligodendrocyte Precursor Maturation and Myelin Regeneration in a Cuprizone-Induced Long-Term Demyelination Animal Model

“…Currently, chronic demyelination is induced by a 12-week cuprizone treatment [ 40 , 41 ]. However, in these cases, the remyelination fails or is insufficient [ 43 , 44 , 45 , 87 ] due to the reduced expression of Trem2 resulting in an impaired clearance of myelin debris from microglia. Therefore, we opted for a 10-week cuprizone treatment to mimic a chronic course of demyelination.…”

Lanthionine Ketimine Ethyl Ester Accelerates Remyelination in a Mouse Model of Multiple Sclerosis

“…LKE reduced microglial activation in vitro ( Hensley et al, 2010a ) as well as in vivo in mouse models of PD ( Togashi et al, 2020 ); spinal cord injury ( Kotaka et al, 2017 ); and AD ( Hensley et al, 2013 ). Both astrocyte and microglial responses have been shown to modulate remyelination in the CPZ model ( Gudi et al, 2014 ; Sen et al, 2022 ). Phagocytosis of myelin debris (Cignarella et al, 2020 ; Ding et al, 2021 ; Shen et al, 2021 ) and production of protective factors (Aryanpour et al, 2021 ) can enhance remyelination, while production of inflammatory mediators can impede remyelination (Thomas & Pasquini, 2018 ).…”