Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons

Abstract

After stroke, there is a rapid necrosis of all cells in the infarct, followed by a delayed loss of neurons both in brain areas surrounding the infarct, known as ‘selective neuronal loss’, and in brain areas remote from, but connected to, the infarct, known as ‘secondary neurodegeneration’. Here we review evidence indicating that this delayed loss of neurons after stroke is mediated by the microglial phagocytosis of stressed neurons. After a stroke, neurons are stressed by ongoing ischemia, excitotoxicity and/or inflammation and are known to: (i) release “find-me” signals such as ATP, (ii) expose “eat-me” signals such as phosphatidylserine, and (iii) bind to opsonins, such as complement components C1q and C3b, inducing microglia to phagocytose such neurons. Blocking these factors on neurons, or their phagocytic receptors on microglia, can prevent delayed neuronal loss and behavioral deficits in rodent models of ischemic stroke. Phagocytic receptors on microglia may be attractive treatment targets to prevent delayed neuronal loss after stroke due to the microglial phagocytosis of stressed neurons.

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

“…TMEM16F is a physiological fusogen that under normal circumstances mediates the fusion of trophoblasts, indicating that viral overactivation of this protein may trigger placental pathology ( Zhang et al., 2020 ). In the brain, TMEM16F is expressed primarily in neurons and microglia, suggesting that viruses may trigger pathological cell-cell fusion and aberrant microglial behavior ( Zhang et al., 2020 ; Brown, 2021 ). For example, pathological multinucleated microglia with increased phagocytic capacity were documented in AD, suggesting that these cells can eliminate viable neurons ( Kemp et al.…”

Neu1 Is Released From Activated Microglia, Stimulating Microglial Phagocytosis and Sensitizing Neurons to Glutamate

“…Microglia are specialized phagocytes of the central nervous system (CNS), and may phagocytose neurons, synapses and dendrites during brain development ( Vilalta and Brown, 2018 ). However, excessive phagocytosis or secretion of proinflammatory factors by microglia may lead to neuronal or synaptic loss, which may contribute to CNS pathologies such as brain ischemia or Alzheimer’s disease ( Brown, 2021 ; Butler et al, 2021 ). Microglia may be activated by lipopolysaccharide (LPS, also known as endotoxin), lipoteichoic acid (LTA), rotenone or amyloid-β (Aβ), thereby stimulating microglial phagocytosis and toxicity to neurons ( Kinsner et al, 2005 ; Neher et al, 2011 ; Emmrich et al, 2013 ; Neniskyte and Brown, 2013 ).…”

Knockout of the P2Y6 Receptor Prevents Peri-Infarct Neuronal Loss after Transient, Focal Ischemia in Mouse Brain

“…Activation of complement component C3 produces potent opsonins to tag neurons for phagocytosis, and an inhibitor of C3 activation, Crry, prevented phagocytosis of stressed-but-salvageable neurons in peri-infarct areas, and reduced functional deficits in a mouse model of stroke [34,35]. Thus, there is evidence from a variety of sources that microglial phagocytosis may contribute to neuronal loss after stroke (as reviewed in [9]).…”

“…The mechanisms of delayed neuronal death after stroke are unclear [2,7], but one potential mechanism is microglial phagocytosis of live neurons, resulting in death of the engulfed neurons [8,9]. Microglial phagocytosis of live neurons and neuronal parts is known to occur during development, physiology, and pathology [10][11][12][13].…”