Microglial phagocytosis of neurons in neurodegeneration, and its regulation

Abstract

There is growing evidence that excessive microglial phagocytosis of neurons and synapses contributes to multiple brain pathologies. RNA‐seq and genome‐wide association (GWAS) studies have linked multiple phagocytic genes to neurodegenerative diseases, and knock‐out of phagocytic genes has been found to protect against neurodegeneration in animal models, suggesting that excessive microglial phagocytosis contributes to neurodegeneration. Here, we review recent evidence that microglial phagocytosis of live neurons and synapses causes neurodegeneration in animal models of Alzheimer's disease and other tauopathies, Parkinson's disease, frontotemporal dementias, multiple sclerosis, retinal degeneration and neurodegeneration induced by ischaemia, infection or ageing. We also review factors regulating microglial phagocytosis of neurons, including: nucleotides, frackalkine, phosphatidylserine, calreticulin, UDP, CD47, sialylation, complement, galectin‐3, Apolipoprotein E, phagocytic receptors, Siglec receptors, cytokines, microglial epigenetics and expression profile. Some of these factors may be potential treatment targets to prevent neurodegeneration mediated by excessive microglial phagocytosis of live neurons and synapses.

Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice

“…The inflammatory response of the brain is mainly mediated by microglia, which are resident brain macrophages that when inflamed can kill neurons by multiple mechanisms, including by phagocytosing neurons [1][2][3]. Dead neurons do not accumulate significantly in neurodegenerative diseases, and one potential cause of this is that neurons are phagocytosed when alive [5,6]. Phagocytosis of live cells normally results in death of the engulfed cells, a type of cell death termed phagoptosis, i.e., cell death by phagocytosis [7].…”

Celiac Disease Defined by Over-Sensitivity to Gliadin Activation and Superior Antigen Presentation of Dendritic Cells

“…Through the careful decipherment of flow cytometric readouts, reduced CD33 levels were associated with elevated levels of the co-stimulatory partner CD64. The significance of this finding needs further elucidation given that CD33 represents a lineage marker associated with phagocytotic inhibition [ 41 , 42 ] and CD64 is an early onset marker of clinical infection [ 43 ]. Nevertheless, it may be of potential diagnostic and therapeutic value for CeD remediation.…”

The Phagocytic Code Regulating Phagocytosis of Mammalian Cells

“…The microglial phagocytic receptor TREM2 mediates synaptic pruning, as TREM knockout mice have reduced microglial internalisation of synapses and increased synaptic density ( 347 ). Excessive microglial phagocytosis of synapses may contribute to neurodegeneration ( 348 , 349 ), emphasising the clinical importance for better understanding the phagocytic code regulating synapse removal.…”

“…In other pathologies, phagocytosis plays detrimental roles. In Alzheimer’s disease, excessive phagocytosis of synapses and neurons by microglia may contribute to disease progression, and blocking phagocytosis can ameliorate animal models of the disease ( 348 , 349 ). Excessive phagocytosis of neurons and/or synapses within the brain has been linked to several other neuropathologies, including Parkinson’s disease, frontotemporal dementia ( 364 ), schizophrenia ( 166 ), glaucoma ( 365 ) and disease resulting from West Nile Virus infection ( 342 ).…”