Targeting Microglia-Synapse Interactions in Alzheimer's Disease

Abstract

In this review, we focus on the emerging roles of microglia in the brain, with particular attention to synaptic plasticity in health and disease. We present evidence that ramified microglia, classically believed to be "resting" (i.e., inactive), are instead strongly implicated in dynamic and plastic processes. Indeed, there is an intimate relationship between microglia and neurons at synapses which modulates activity-dependent functional and structural plasticity through the release of cytokines and growth factors. These roles are indispensable to brain development and cognitive function. Therefore, approaches aimed at maintaining the ramified state of microglia might be critical to ensure normal synaptic plasticity and cognition. On the other hand, inflammatory signals associated with Alzheimer's disease are able to modify the ramified morphology of microglia, thus leading to synapse loss and dysfunction, as well as cognitive impairment. In this context, we highlight microglial TREM2 and CSF1R as emerging targets for disease-modifying therapy in Alzheimer's disease (AD) and other neurodegenerative disorders.

Keywords: Alzheimer’s disease; Cytokines; Long-term potentiation; Microglia; Neuroinflammation; Synaptic Plasticity.

Figure 1

The dual role of microglial phenotypes in Alzheimer’s disease (AD). Depending on the received stimuli, resting microglia can shift to either neurotoxic (M1) or neuroprotective (M2) phenotype. Activated M2 microglia participate in the clustering of amyloid beta (Aβ) plaques and their consequent phagocytosis. Overproduction of pro-inflammatory cytokines by M1 can reactivate microglia-mediated pruning, aided by C1q and C3, leading to pathological synaptic loss. Minocycline can modulate the pathological activation of M1 phenotype and lock the pro-inflammatory mediators’ release, thereby reducing inflammation. The modulation of colony-stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells 2 (TREM2) R47H receptors expressed by microglia, e.g., through CSF1R inhibitor Pexidartinib (PLX3397) administration, could exert a protective role in preventing microglia-mediated pruning reactivation.