Neurophagy, the phagocytosis of live neurons and synapses by glia, contributes to brain development and disease

Abstract

It was previously thought that neurons were phagocytosed only when dead or dying. However, it is increasingly clear that viable synapses, dendrites, axons and whole neurons can be phagocytosed alive (defined here as neurophagy), and this may contribute to a wide range of developmental, physiological and pathological processes. Phagocytosis of live synapses, dendrites and axons by glia contributes to experience‐dependent sculpting of neuronal networks during development, but excessive phagocytosis of synapses may contribute to pathology in Alzheimer's disease, schizophrenia and ageing. Neurons can expose phosphatidylserine or calreticulin, which act as ‘eat me’ signals provoking phagocytosis via microglial receptors, whereas sialylation of neuronal surfaces acts as a ‘don't eat me’ signal that inhibits phagocytosis and desialylation can provoke phagocytosis. Opsonins, such as complement components and apolipoproteins, are released during inflammation and enhance engulfment. Phagocytosis of neurons is seen in multiple human diseases, but it is as yet unclear whether inhibition of phagocytosis will be beneficial in treating neurological diseases. Here we review the signals regulating glial phagocytosis of live neurons and synapses, and the involvement of this phagocytosis in development and disease.

Activated microglia desialylate their surface, stimulating complement receptor 3‐mediated phagocytosis of neurons

“…They are of myeloid origin and therefore related to phagocytes in the periphery (Saijo & Glass, ). Microglia defend the brain against invading pathogens, but also engulf and remove apoptotic neurons, necrotic neurons, debris, protein aggregates, synapses and axons (Rabinowicz & Courten‐Myers, ; Vilalta & Brown, ). Microglia phagocytose less‐active synapses during development to shape neuronal networks, and too little of this “synaptic pruning” may contribute to autism, and too much pruning may contribute to schizophrenia (Neniskyte & Gross, ; Sekar et al, ).…”

“…Microglia phagocytose less‐active synapses during development to shape neuronal networks, and too little of this “synaptic pruning” may contribute to autism, and too much pruning may contribute to schizophrenia (Neniskyte & Gross, ; Sekar et al, ). During neurodegenerative diseases, such as Alzheimer's disease, excessive microglial phagocytosis of synapses and live neurons may cause the neurodegeneration (Vilalta & Brown, ). Thus, it is important to understand how microglial phagocytosis is regulated.…”

Microglial distribution, branching, and clearance activity in aged rat hippocampus are affected by astrocyte meshwork integrity: evidence of a novel cell‐cell interglial interaction

“…The presence of amyloidb (Ab) peptides induces the production and release of proinflammatory cytokines by neurons and astrocytes (4,5) which shift microglia from a surveillance/maintenance mode into active phagocytosis (6)(7)(8). Microglia are the immunocompetent cells in the CNS and are also involved in removal of damaged neurons and dysfunctional synapses in both normal and pathologic nervous tissue (9)(10)(11)(12)(13)(14). Activated microglia perform phagocytosis of Ab deposits, contributing to Ab clearance and removal of cytotoxic debris from the brain (1,6,12,(14)(15)(16).…”

“…Microglia are the immunocompetent cells in the CNS and are also involved in removal of damaged neurons and dysfunctional synapses in both normal and pathologic nervous tissue (9)(10)(11)(12)(13)(14). Activated microglia perform phagocytosis of Ab deposits, contributing to Ab clearance and removal of cytotoxic debris from the brain (1,6,12,(14)(15)(16). However, sustained microglial activation may increase Ab deposition, intensify neurodegeneration (2,3), and phagocytose healthy neurons (10,11,14,17,18).…”

Different faces of neurodegeneration

“…The authors describe in detail the signals regulating glial phagocytosis of live neurons and synapses and the involvement of this phagocytosis in development and disease [7]. This process can help to explain the role of neuroinflammation in Alzheimer's disease and schizophrenia.…”