Neurodegeneration and demyelination in multiple sclerosis

Abstract

Progressive multiple sclerosis (PMS) is an immune-initiated neurodegenerative condition that lacks effective therapies. Although peripheral immune infiltration is a hallmark of relapsing-remitting MS (RRMS), PMS is associated with chronic, tissue-restricted inflammation and disease-associated reactive glial states. The effector functions of disease-associated microglia, astrocytes, and oligodendrocyte lineage cells are beginning to be defined, and recent studies have made significant progress in uncovering their pathologic implications. In this review, we discuss the immune-glia interactions that underlie demyelination, failed remyelination, and neurodegeneration with a focus on PMS. We highlight the common and divergent immune mechanisms by which glial cells acquire disease-associated phenotypes. Finally, we discuss recent advances that have revealed promising novel therapeutic targets for the treatment of PMS and other neurodegenerative diseases.

Keywords: astrocytes; chronic inflammation; complement; inhibitory factors; microglia; neuroprotection; oligodendrocytes; progressive multiple sclerosis; reactive glia; remyelination.

Figure 1:. Complement in inflammatory demyelination.

A) The classical complement cascade. B) Macroscopic deposition of antibody and complement in demyelinating white matter lesions. Antibodies in the perivascular CSF-filled space escape into the brain parenchyma, allowing for deposition of microglial (MG)-secreted C1q and activation of astrocyte (Ast)-secreted C3 into C3a and C3b at the chronic active edge. C) Complement locally influences glia towards reactive phenotypes. Deposition of C3b onto myelin can be recognized by microglial CD11b, resulting in phagocytosis. Stimulation of C3aR with C3a results in increases of HIF-1a as well as alterations in phagocytosis depending on the duration of the stimulation. Made in BioRender.

Figure 2:. Proposed Mechanisms of Glial Neurotoxicity in PMS.

A) Normal healthy CNS environment, with CD47 (a “Don’t Eat Me” signal) signaling through microglial Sirpα to halt phagocytosis of synapses. Homeostatic astrocytes support neuronal metabolism and ensure that neurons have sufficient resources to thrive. B) The setting of neuroinflammation in the CNS. Reactive astrocytes upregulate glycolysis and translation, leading to diversion of resources away from neurons and towards glia, resulting in a state of virtual hypoxia. Astrocytes may directly mediate neurodegeneration through secretion of Long Chain Fatty Acids (LCFAs) and TNF among other cytokines, while microglial Galectin-3 enhances the neurotoxicity of oxidized phosphatidylcholine (OxPC). Meanwhile, stressed neurons downregulate CD47 concurrent with increases in local complement deposition, resulting in phagocytosis of synapses which may lead to neurodegeneration. Made in BioRender.

Figure 3:. Pharmacologic efforts to promote myelination and neuroprotection.

A) An oligodendroglial cell showing the targets for drugs that have been shown to promote oligodendroglial differentiation, maturation, and/or myelination. Several identified inhibitory factors of remyelination are also depicted with flathead arrows directed to the drugs that these inhibitors been shown to target. Notably, DMH1 is not inhibited by fibrinogen and Sephin1 upregulates the ISR even in the presence of IFNγ. B) Selection of key drugs and molecules that may help downregulate neurotoxic and oligotoxic reactive glia. Also displayed are pharmacologic inhibitors of the non-apoptotic cell death pathways necroptosis, ferroptosis, and parthanatos. Made in BioRender.