Targeting Microglia-Synapse Interactions in Alzheimer’s Disease

Gaia Piccioni,Dalila Mango,Robert Nisticò,Massimo Corbo,Amira Saidi

doi:10.3390/ijms22052342

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.

Highlights

Synaptic plasticity refers to the capability of experience to modify neural circuit function and thereby influence thinking, feeling, and behavioral patterns
Increasing findings suggest the chronic activation of microglia is a common pathological feature of neurodegenerative disorders characterized by neuroinflammation, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS)
We will give an overview of genes expressed in microglia, and focus on the colony-stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells 2 (TREM2)

Summary

Introduction

Synaptic plasticity refers to the capability of experience to modify neural circuit function and thereby influence thinking, feeling, and behavioral patterns. The close interactions between microglia and synapses lead to the so-called synaptic stripping hypothesis [6], a process in which microglia can selectively eliminate dysfunctional synapses. This microglia-mediated synapse removal, normally associated with activity-dependent refinement during neurodevelopment, can be reactivated in aging or in neurodegenerative diseases [7]. The present review focuses on the emerging cellular and molecular mechanisms linking changes in microglia functionality to synaptic alterations in AD, and highlights the microglia–synapse interaction as a potential target for the treatment and prevention of AD

The Synaptic Basis of AD

Microglia in Brain Physiology

Microglia in Pathological Conditions

Modulation of Microglia Activation

Gene Expression Profiling

Conclusions