Microglia in neurodegeneration

Abstract

The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system. Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a defense function necessary for responding to such changes and providing neuroprotection. Microglia use a defined armamentarium of genes to perform these tasks. In response to specific stimuli, or with neuroinflammation, microglia also have the capacity to damage and kill neurons. Injury to neurons in Alzheimer's, Parkinson's, Huntington's, and prion diseases, as well as in amyotrophic lateral sclerosis, frontotemporal dementia, and chronic traumatic encephalopathy, results from disruption of the sentinel or housekeeping functions and dysregulation of the defense function and neuroinflammation. Pathways associated with such injury include several sensing and housekeeping pathways, such as the Trem2, Cx3cr1 and progranulin pathways, which act as immune checkpoints to keep the microglial inflammatory response under control, and the scavenger receptor pathways, which promote clearance of injurious stimuli. Peripheral interference from systemic inflammation or the gut microbiome can also alter progression of such injury. Initiation or exacerbation of neurodegeneration results from an imbalance between these microglial functions; correcting such imbalance may be a potential mode for therapy.

Fig. 1 |. Microglia in a normal mouse brain.

a–c, Mouse microglia, stained here with anti-CD11b, have distinct processes that are constantly moving in the area around the cell body, and form a network of cells that spans most of the CNS, including the (a) cortex (b) hippocampus, and (c) cerebellum. d, Three-dimensional image of a mouse microglia with summary of gene ontology analysis of the sensome genes. e, Heatmap showing comparative expression of microglial sensome genes identified by RNA-seq data using the Allen Brain Atlas in situ hybridization dataset. Most of the genes are similarly expressed in most areas of the brain, except for two small clusters that appear to have differential expression in the brain stem. ECM, extracellular matrix.

Fig. 2 |. Three proposed functional states of microglia.

a, Nurturer state: microglia (left) stained for Cd11b (brown) in a normal brain are highly ramified and evenly spaced throughout the brain parenchyma. In their nurturer role they maintain milieu homeostasis, participate in synaptic remodeling and migration, and remove apoptotic neurons, all mediated by specific receptors and receptor-linked pathways. b, Sentinel state: micrograph taken from a video using two-photon microscopy from a Cx3cr1-GFP mouse with a cranial window shows a cluster of green microglia with abundant processes. The video from which this micrograph was taken (Supplementary Video 1) shows that microglia (green) processes are in constant motion, surveilling their surroundings. Focal laser-induced injury initiates microglia response, with those microglia closest to the site of injury displaying polarization of surveilling processes toward the area of injury. Microglia sensing is mediated by proteins encoded by sensome genes, which are portals for microglia to perform their housekeeping and host-defense functions. c, Warrior state: microglia (left) stained for Cd11b (brown) accumulate around Aβ deposits stained with thioflavin-S (green), where they are observed to be two- to fivefold denser than in neighboring areas. The warrior morphology becomes stockier and less ramified, and defense against infectious pathogens and injurious-self proteins including Aβ is mediated through microglial Fc receptors, TLRs, viral receptors, and antimicrobial peptides. Sensing is a prerequisite for microglia to perform their housekeeping and host-defense functions.

Fig. 3 |. Effectors of microglia function associated with neurodegeneration.

Two common themes for microglia’s roles in neurodegenerative diseases emerge. As microglia perform their normal sentinel function, they encounter aberrant or misfolded proteins such as Aβ, aggregated α-synuclein, oxidized or mSOD1, or PrP^sc. In response to these toxic stimuli, microglia perform their host-defense function, attempting to clear these agents via SRs and other PRRs. The nature of the aberrant proteins or their persistent production disrupts microglial housekeeping functions and dysregulates microglial host-defense functions, leading to an exaggerated proinflammatory response, neurotoxicity, and neurodegeneration. A second theme is that in some neurodegenerative diseases, such as AD, ALS, and HD, mutations in specific genes cause self-autonomous dysregulation of host defense, thereby initiating or exaggerating proinflammatory responses, resulting in neurotoxicity and neurodegeneration. For example, mutations in TDP-43, progranulin, and Trem2 affect phagocytosis and associated degradation pathways (purple), whereas mutations in mSOD and HTT affect inflammasome activation and neuronal killing pathways (red). Mutations in C9orf72 affect both phagocytosis and inflammasome pathways. MMPs, matrix metalloproteases; AβDE, Aβ-degrading enzymes.

Fig. 4 |. How microglia damage or kill neurons: There are several direct and indirect tools used by microglia to perform this task.

When microglia interact with ligands such as an infectious pathogen, Aβ, PrP^Sc, aggregated α-synuclein, or mSOD1, several pathways are activated. NADPH oxidase produces superoxide and derivative oxidants. Nitric oxide and its derivatives are produced by iNOS. Glutamate, cathepsin B, and other proteases are released, or phagocytic killing of stressed neurons occurs. Oxidative lipid damage reduces membrane fluidity and membrane potential and increases ion permeability, resulting in organelle swelling, loss of membrane depolarization, and rupture of the plasma membrane, leading to necrosis. Microglia also utilize indirect means to kill and damage neurons, including release of TNF, which stimulates NMDA receptor activity, or reduced production of nutritive BDNF and IGF.