Glia in Neurodegeneration: The Housekeeper, the Defender and the Perpetrator

Abstract

Over the past decade, research has unveiled the intimate relationship between neuroinflammation and neurodegeneration. Microglia and astrocytes react to brain insult by setting up a multimodal inflammatory state and act as the primary defenders and executioners of neuroinflammatory structural and functional changes. Microglia and astrocytes also play critical roles in the maintenance of normal brain function. This intricate balance of homeostatic and neuroinflammatory functions can influence the onset and the course of neurodegenerative diseases. The emergent role of the microglial-astrocytic axis in neurodegenerative disease presents many druggable targets that may have broad therapeutic benefits across neurodegenerative disease. Here, we provide a brief review of the basal function of both microglia and astrocytes, how they are changed in disease states, the significant differences between mouse and human glia, and use of human induced pluripotent stem cells derived from patients to study cell autonomous changes in human astrocytes and microglia.

Neuroinflammation in Alzheimer’s Disease

“…They also regulate the maturation of neurons and help maintain their function [ 147 , 148 ]. They are found in various states of activation and can be neuroprotective (reducing inflammation and stimulating repair) or neurotoxic (promoting inflammation that may result in neurodegeneration) [ 149 , 150 ]. They respond to inflammatory molecules such as cytokines and chemokines and are able to detect aggregated proteins such as Aβ [ 148 , 151 , 152 ].…”

The neurogliovascular unit in hepatic encephalopathy

“…As they link the vasculature to neurons in the so-called neurovascular coupling, astrocytes can regulate blood flow based on local neuronal needs (17). They additionally connect with neurons to provide trophic support (17), aid in neurotransmitter reuptake and synapse regulation (21,23).…”

“…Microglia are the resident CNS immune cells. In homeostatic conditions, they continuously scan the local environment for synaptic activity, pathogen presence and injury (23). Additionally, their housekeeping function consists of phagocytosis of dead/dying cells and debris, as well as synaptic remodelling and myelin homeostasis (24).…”

“… 17 They additionally connect with neurons to provide trophic support, 17 and aid in neurotransmitter reuptake and synapse regulation. 21 , 23 …”

Developmental Alterations in Adult‐Onset Neurodegenerative Disorders: Lessons from Polyglutamine Diseases

“…Astrocytic, microglial, and oligodendrocytic pathologies also occur early, which suggest a role for glial pathology as well. 10,11 In fact, changes in gene expression can be observed in early postnatal life. Some of these events at the levels of proteins and gene expression may well be compensatory, 12,13 but pathogenic processes are definitely at play given that delaying the expression of mutant polyglutamine proteins or rescuing early transcriptional deficits prevents later degeneration.…”