Central nervous system diseases related to pathological microglial phagocytosis

Abstract

Microglia are important phagocytes of the central nervous system (CNS). They play an important role in protecting the CNS by clearing necrotic tissue and apoptotic cells in many CNS diseases. However, recent studies have found that microglia can phagocytose parts of neurons excessively, such as the neuronal cell body, synapse, or myelin sheaths, before or after the onset of CNS diseases, leading to aggravated injury and impaired tissue repair. Meanwhile, reduced phagocytosis of synapses and myelin results in abnormal circuit connections and inhibition of remyelination, respectively. Previous studies focused primarily on the positive effects of microglia phagocytosis, whereas only a few studies have focused on the negative effects. In this review, we use the term "pathological microglial phagocytosis" to refer to excessive or reduced phagocytosis by microglia that leads to structural or functional abnormalities in target cells and brain tissue. The classification of pathological microglial phagocytosis, the composition, and activation of related signaling pathways, as well as the process of pathological phagocytosis in various kinds of CNS diseases, are described in this review. We hypothesize that pathological microglial phagocytosis leads to aggravation of tissue damage and negative functional outcome. For example, excessive microglial phagocytosis of synapses can be observed in Alzheimer's disease and schizophrenia, leading to significant synapse loss and memory impairment. In Parkinson's disease, ischemic stroke, and traumatic brain injury, excessive microglial phagocytosis of neuronal cell bodies causes impaired gray matter recovery and sensory dysfunction. We therefore believe that more studies should focus on the mechanism of pathological microglial phagocytosis and activation to uncover potential targets of therapeutic intervention.

Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons

“…It used to be thought that only dead or dying neurons are phagocytosed, but we now know synapses, dendrites, axons, neuronal precursors, newborn neurons and 'excess' neurons are all phagocytosed alive during development [26]. Microglial phagocytosis of neurons and neuronal parts continues in the adult brain, mediating both physiology and pathology [24,27].…”

The Role of Microglial Phagocytosis in Ischemic Stroke

“…Microglia, the professional phagocyte of the brain, are capable of engulfing cell debris and pruning synapses in developing brain and various cerebral diseases ( 5 ). Despite being less commonly known, a growing body of literature has linked microglial phagocytosis with stroke recovery.…”

Microglia in Neurodegenerative Events—An Initiator or a Significant Other?

“…This has been termed "phagoptosis" [117]. Negative effects of microglial phagocytosis can be driven by unwarranted or misdirected phagocytosis that can either be excessive phagocytosis or reduced phagocytosis [118]. Excessive phagocytosis of synapses, neuronal cell bodies, or myelin sheath can be detrimental to tissue and functional recovery.…”