Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer’s disease via MFG-E8

Abstract

Synapse loss correlates strongly with cognitive decline in Alzheimer's disease, but the 20 mechanisms underpinning this phenomenon remain unclear. Recent evidence from mouse models points to microglial cells as mediators of synapse removal, and human genetic evidence implicates microglia in disease risk. Here we demonstrate that microglia from human postmortem brain contain synaptic proteins and that greater amounts are observed in microglia from Alzheimer's compared to non-diseased brain tissue. Further, we observe that primary human 25 adult microglia phagocytose synapses isolated from human brain, and that AD brain-derived synapses are phagocytosed more rapidly and abundantly than controls. Together, these data show that synapses in the human AD brain are more prone to ingestion by microglia. Our findings provide evidence from human tissue implicating altered microglial-mediated synaptic uptake in AD pathobiology. 30One Sentence Summary: AD alters synapse ingestion by microglia

Knock-in models related to Alzheimer’s disease: synaptic transmission, plaques and the role of microglia

“…We recently proposed that it is more likely that synaptic toxicity imparted by Aβ induces microglia to phagocytose damaged synapses rather than Aβ, limiting the spread of damage [18]. Supporting the suggestion that microglia phagocytose synapses, a recent prepublication shows adult human microglia containing synaptic proteins and that synapses derived from Alzheimer's disease brain are phagocytosed more readily [56]. Alternative roles for microglia in Aβ handling have been proposed, including compacting Aβ via TREM2dependent mechanisms [57,58] or clearing Αβ via non-phagocytic mechanisms [summarised in 52].…”

Ground state depletion microscopy as a tool for studying microglia–synapse interactions

“…Microglia–synaptic interactions in physiological and diseased states are increasingly appreciated. A preprint of one study using confocal microscopy demonstrated increased co‐localization of the endosomal/lysosomal marker CD68, expressed by myeloid cells including microglia, and the presynaptic marker synapsin‐I in post‐mortem human tissue (Tzioras et al., 2019). Here we have used GSDIM to demonstrate increased co‐localization of presynaptic material by microglia in post‐mortem human AD tissue compared to healthy controls and other non‐demented controls with high levels of AD‐type pathology.…”

“…This process has two components, an initial detachment of afferent axonal endings from the neuronal somatic membrane and dendrites, followed by the displacement of the detached terminals by microglial cells. It is the latter process followed by astroglial insulation of neurons ) that appears to be responsible for the long-lasting functional deficit observed in patients with Bell's palsy (Graeber et al, 1993) Paolicelli et al, 2011;Parkhurst et al, 2013;Schafer et al, 2012;Svahn et al, 2014;Tremblay et al, 2010;Tzioras et al, 2019;Vasek et al, 2016;Wake et al, 2009;Wang et al, 2020;Weinhard et al, 2018;Zhan et al, 2014). The majority of studies monitoring microglial interactions with synapses have been conducted using confocal and two-photon microscopy.…”

Synapse development is regulated by microglial THIK-1 K+channels

“…Synapse loss is a strong indicator of cognitive decline (60)(61)(62). Synaptic deficits precede amyloid deposition in animal models of dementia (63) and microglial phagocytosis of synaptic material is increased in Alzheimer's patients (52). Ablation of microglia rescues synaptic loss and reduces memory impairment in mouse models of dementia (64).…”