Microglia-Mediated Synapse Loss in Alzheimer's Disease

Abstract

Microglia are emerging as key players in neurodegenerative diseases, such as Alzheimer's disease (AD). Thus far, microglia have rather been known as modulator of neurodegeneration with functions limited to neuroinflammation and release of neurotoxic molecules. However, several recent studies have demonstrated a direct role of microglia in "neuro" degeneration observed in AD by promoting phagocytosis of neuronal, in particular, synaptic structures. While some of the studies address the involvement of the β-amyloid peptides in the process, studies also indicate that this could occur independent of amyloid, further elevating the importance of microglia in AD. Here we review these recent studies and also speculate about the possible cellular mechanisms, and how they could be regulated by risk genes and sleep. Finally, we deliberate on possible avenues for targeting microglia-mediated synapse loss for therapy and prevention.Dual Perspectives Companion Paper: Alzheimer's Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models by William M. Vanderheyden, Miranda M. Lim, Erik S. Musiek, and Jason R. Gerstner.

Keywords: Alzheimer's disease; amyloid; clearance; microglia; phagocytosis; synaptic pruning.

Figure 1.

Diagram depicting the role of microglia (yellow) in supporting synapse homeostasis under physiological conditions (left). Pathological role (right) is influenced either genetically through late-onset AD risk genes or through sleep deprivation. Top right, Phagocytic uptake of synaptic structures by microglia, aided by Aβ, complement molecules, C1q and C3. A possible role for APOE is here proposed. Inset (zoomed), Possible tagging mechanism of synaptic structures by Aβ and complement. Bottom right, Synapse loss mediated by soluble factors or by loss of trophic support.