Modulation of Glial Function in Health, Aging, and Neurodegenerative Disease

Abstract

In the central nervous system (CNS), glial cells, such as microglia and astrocytes, are normally associated with support roles including contributions to energy metabolism, synaptic plasticity, and ion homeostasis. In addition to providing support for neurons, microglia and astrocytes function as the resident immune cells in the brain. The glial function is impacted by multiple aspects including aging and local CNS changes caused by neurodegeneration. During aging, microglia and astrocytes display alterations in their homeostatic functions. For example, aged microglia and astrocytes exhibit impairments in the lysosome and mitochondrial function as well as in their regulation of synaptic plasticity. Recent evidence suggests that glia can also alter the pathology associated with many neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). Shifts in the microbiome can impact glial function as well. Disruptions in the microbiome can lead to aberrant microglial and astrocytic reactivity, which can contribute to an exacerbation of disease and neuronal dysfunction. In this review, we will discuss the normal physiological functions of microglia and astrocytes, summarize novel findings highlighting the role of glia in aging and neurodegenerative diseases, and examine the contribution of microglia and astrocytes to disease progression.

Keywords: Alzheimer’s disease; Parkinson’s disease; aging; astrocytes; glia; microbiome; microglia; neurodegeneration.

Figure 1

Role of microglia and astrocytes in health, age, and neurodegenerative disease. Microglia and astrocytes release cytokines and chemokines in the neuronal milieu, adopting different responses depending on their surrounding environment. Their responses modulate each other’s activity as well as the activity of neurons and other nearby cell types. In this schematic, the contributions of microglia and astrocytes as well as their influence on neuronal outcomes are identified in health, aging, and neurogenerative disease. Microglial and astrocyte influences in neuropathology are also indicated as pathological (orange) or neuroprotective (blue). OPC, oligodendrocyte progenitor cells; BBB, blood-brain barrier; CNS, central nervous system; LTP, long-term potentiation; Aβ, amyloid-β; AD, Alzheimer’s disease; α-syn, α-synuclein; PD, Parkinson’s disease. *Created with Biorender.com.

Figure 2

Microbiome influence on microglia and astrocyte function in health, age, and neuropathology. Multiple factors affect an individual’s microbiome composition including diet, age, and disease. In the distal intestine, gut metabolites can cross the gut epithelium and modulate the immune system, which can influence the function of microglia and astrocytes in health, age, and neurodegenerative diseases. Functions of microglia and astrocytes that are altered in mice who have had their microbiome altered, contain a microbiome or lack thereof have been identified. Aβ, amyloid-β; GF, germ-free; ABX, antibiotic; AD, Alzheimer’s disease; EAE, experimental autoimmune encephalomyelitis; CNS, central nervous system; DC, dendritic cell; HF, high-fat; TMAO, trimethylamine N-oxide; AHR, aryl hydrocarbon receptor. *Created with Biorender.com.