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.

Microglia ablation alleviates myelin-associated catatonic signs in mice

“…Such a mechanism would be in line with the emerging role of microglia for behavioral phenotypes (15)(16)(17)(18). Here, we demonstrate an unexpectedly high, age-associated prevalence of catatonic signs in more than 25% of deeply phenotyped schizophrenic subjects.…”

“…The sudden loss of motor control in catatonia, followed by an equally sudden regaining of control -often within seconds -ultimately suggests a dysfunction of synaptic circuitry. Importantly, we could show that chronic neuroinflammation in the subcortical white matter progresses into the cingulate cortex, where activated microglia are known to perturb normal synaptic function (16). The production of nitric oxide and axonal conduction blocks, for instance, constitute well-established links between activated microglia and neurodegeneration (52).…”

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

“…Apolipoprotein E allele ε4 (APOE*ε4), the strongest known genetic risk factor for AD, is highly expressed in microglia and has been shown to influence microglial activation in response to Aβ deposition (58). Microglia also express complement receptors and mediate synaptic pruning in the developing brain (59,60). Classical complement protein C1q is induced in the brains of AD mice (61,62) and mediates early synapse loss in AD mouse models (63).…”

Assessing amyloid-β, tau, and glial features in Lothian Birth Cohort 1936 participants post-mortem

“…We have broadened the extent of post-mortem pathology investigated from well-established amyloid and tau analysis to the quantification of glial cell numbers. Specifically, microglia and astrocytes are immune cells essential for maintaining neuronal health through a range mechanisms, including synaptic pruning [17] [18], phagocytosis [19], and myelin regeneration [20]. During ageing, however, microglia and astrocytes become over-activated [21] [22] resulting in neuroinflammation and neurodegeneration [23] [24] [25].…”