Microglia Function in the Central Nervous System During Health and Neurodegeneration

Abstract

Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment. They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS. Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses. Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration. Recent observations about microglia ontogeny combined with extensive gene expression profiling and novel tools to study microglia biology have allowed us to characterize the spectrum of microglial phenotypes during development, homeostasis, and disease. In this article, we review recent advances in our understanding of the biology of microglia, their contribution to homeostasis, and their involvement in neurodegeneration. Moreover, we highlight the complexity of targeting microglia for therapeutic intervention in neurodegenerative diseases.

Keywords: homeostasis; microglia; neurodegeneration; phenotypes; receptors; regulation.

Figure 1

Schematic representation of the transcriptional and functional programs of microglia in homeostatic conditions (M0), during aging, and in models of neurodegeneration. Abbreviations: AD, Alzheimer disease; ALS, amyotrophic lateral sclerosis; PD, Parkinson disease.

Figure 2

Regulation of neuronal networks and functions by microglia. Microglia engulf apoptotic neurons via TAM receptor–mediated recognition of GAS6-opsonized cells. Microglia control synaptic plasticity through secretion of ROS, which downregulate AMPA receptors, and BDNF, which engages Trk receptors that modulate activities of various synapses. Microglia can strip synapses that are tagged by complement as well as through CX3CR1-CX3CL1 interactions. Finally, microglia can affect neuronal activity indirectly via astrocytes, which release glutamate and ATP in response to TNF-α released by microglia. Abbreviations: BDNF, brain-derived neurotrophic factor; TAM, Tyro3 and Axl and Mertk receptors; GAS6, growth arrest–specific 6; ROS, reactive oxygen species; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; PP2A, protein phosphatase 2A; Trk, neurotrophic receptor tyrosine kinase.

Figure 3

Neuron-microglia interaction in healthy brain and during Aβ pathology. (a) In a healthy brain, soluble Aβ peptides and small amounts of Aβ seed are cleared by microglia. Microglia receive signals from neurons and secrete neuroprotective factors, control synapse strength, and prune inactive synapses. (b) During Aβ pathology microglia are incapable of removing excessive Aβ aggregates that chronically activate and damage both neurons and microglia. Neurons release excessive neurotransmitters and DAMPs, such as ATP, that further activate microglia. In turn, microglia release inflammatory cytokines that further damage neurons and facilitate Aβ deposition. Aβ-mediated and microglia-mediated insults contribute to neuronal damage, consisting of oxidative stress, reduced axonal transport, weakening of synaptic strength, and excessive elimination of synapses. Abbreviations: DAMP, damage-associated molecular pattern; LTD, long-term depression; LTP, long-term potentiation.

Figure 4

Function of proteins affected by Alzheimer disease–associated mutations in microglia-mediated response to Aβ. Abbreviations: ApoE, apolipoprotein E; APP, amyloid precursor protein; PS, presenilin; PRR, pattern-recognition receptor; TLR, Toll-like receptor.