Repercussions of microglial efferocytosis on neurodegeneration in Alzheimer’s Disease (AD): a double-edged sword and perplexing factor warranting scrutiny in AD research

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) and tau aggregates within the neuronal milieu. To prevent their neurotoxicity, these pathological aggregates will be cleared from the neuronal environment by extracellular, intracellular, and excretory mechanisms. As these compensatory mechanisms become overwhelmed, these left-behind aggregates will instigate neuronal loss via varied downstream signaling events. As a result, neurons undergo cell death through apoptosis and necrosis leading to the accumulation of cellular debris. Timely clearance of this cellular debris is critical, otherwise it can further potentiate neuronal loss by perpetuating pro-inflammatory environment. Microglial cells migrate and engulf these dead neurons by a process known as canonical efferocytosis. On the other hand, normal living neurons will be cleared by microglial cells through extracellular exposure of phosphatidyl serine (PS) under the pathological influence of Aβ and tau through non-canonical efferocytosis. Canonical efferocytosis should be predominant with the absence of the non-canonical efferocytosis during the physiological conditions. Upregulation of cytokines, and chemokines in AD creates a fertile ground for the amplification of non-canonical efferocytosis in parallel to canonical efferocytosis. The preponderance of the non-canonical over canonical pathways leads to exuberant clearance of stressed and normal living neurons along with dead neurons, thereby leading to exacerbated neuronal loss, brain tissue thinning and severe cognitive disturbances in AD. Research efforts should be directed to understanding the factors that fine-tune the balance between these clearance processes. Novel therapeutic strategies that reinforce canonical efferocytosis will be beneficial by improving tissue repair, healing, and regeneration in AD.