New insights on the role of microglia in synaptic pruning in health and disease

Abstract

Recent genome-wide association studies implicate microglia in Alzheimer's disease (AD) pathogenesis; however, their biological significance remains poorly understood. Synapse loss is a significant correlate of cognitive decline that serves as a critical hallmark of AD and other neurodegenerative diseases; however, mechanisms underlying synaptic vulnerability remain elusive. Emerging research on microglia function in the healthy brain is providing new insight into fundamental roles of microglia and immune molecules in brain wiring. Among their many roles, microglia prune developing synapses and regulate synaptic plasticity and function. Here, we review and discuss how this emerging work may provide new insight into how disruptions in microglia-synapse interactions could contribute to synapse loss and dysfunction, and consequently cognitive impairment, in AD.

Figure 1

Potential roles of microglia in the healthy and diseased brain. (a) During early postnatal development, microglia (illustrated in green) help refine excessive synaptic connections (illustrated in blue). Insert highlights microglial engulfment of synaptic elements. Microglia-related proteins including complement proteins and fractalkine have been suggested to mediate this process. (b) In the healthy adult brain, microglial processes are dynamic and continuously survey surrounding synapses. (c) Synapse loss is an early hallmark of AD pathology, thought to be initiated by Aβ oligomers. What microglia do in this early stage of AD remains poorly understood. (d) Late stage AD is characterized by the presence of extracellular plaque deposition, intraneuronal tangle formation and neurodegeneration, often accompanied by significant levels of microgliosis and neuroinflammation. Recent research has given insight into how microglia may impact plaque and plaque-related neuropathology in late stage AD; however, what microglia do in early AD, in particular, how their dynamic interactions with synapses are impacted, is unknown. An intriguing hypothesis is whether microglia and immune-related molecules that mediate synaptic engulfment in the developing brain (a) may be aberrantly reactivated in the AD brain (c) to mediate synapse loss and degeneration.