Inflammation in Alzheimer's disease: Lessons learned from microglia-depletion models

Abstract

Microglia are the primary immune cell of the brain and function to protect the central nervous system (CNS) from injury and invading pathogens. In the homeostatic brain, microglia serve to support neuronal health through synaptic pruning, promoting normal brain connectivity and development, and through release of neurotrophic factors, providing support for CNS integrity. However, recent evidence indicates that the homeostatic functioning of these cells is lost in neurodegenerative disease, including Alzheimer's disease (AD), ultimately contributing to a chronic neuroinflammatory environment in the brain. Importantly, the development of compounds and genetic models to ablate the microglial compartment has emerged as effective tools to further our understanding of microglial function in AD. Use of these models has identified roles of microglia in several pathological facets of AD, including tau propagation, synaptic stripping, neuronal loss, and cognitive decline. Although culminating evidence utilizing these microglial ablation models reports an absence of CNS-endogenous and peripheral myeloid cell involvement in Aβ phagocytosis, recent data indicates that targeting microglia-evoked neuroinflammation in AD may be essential for potential therapeutics. Therefore, identifying altered signaling pathways in the microglia-devoid brain may assist with the development of effective inflammation-based therapies in AD.

Keywords: Alzheimer’s disease; Amyloid; Colony-stimulating factor 1 receptor; Inflammation; Microglia; Spines; Tau.

Figure 1

A schematic of acute and chronic microglial activation in the context of Alzheimer’s disease. In the surveillance state, microglia sample the brain parenchyma to detect anomalous materials, while concomitantly secreting anti-inflammatory factors and pruning unnecessary or weak synapses to support neuronal health. Disturbances in brain homeostasis, such as detection of Aβ, result in the activation of microglia. In the activated state, microglia release pro-inflammatory mediators to recruit other cells to the insult and to phagocytose the detected insult. When the insult is cleared, the inflammatory response resolves via NiReg (Neuroimmune regulatory proteins) activity, and microglia secrete anti-inflammatory factors to promote tissue repair and growth. However, in neurodegenerative diseases, the sustained release of pro-inflammatory mediators, as well as increasing neuronal death, drives the cells into a state of chronic activation. In this state, the homoeostatic functioning of microglia is lost, resulting in an accumulation of aggregated proteins, the stripping of synapses from neurons, as well as further neuronal loss. Importantly, in this reactive state, microglia can be stimulated with certain proteins or methods to induce microglial phagocytosis of Aβ, thereby restoring the phagocytic ability of microglia.