Microglia and Aging: The Role of the TREM2–DAP12 and CX3CL1-CX3CR1 Axes

Abstract

Depending on the species, microglial cells represent 5–20% of glial cells in the adult brain. As the innate immune effector of the brain, microglia are involved in several functions: regulation of inflammation, synaptic connectivity, programmed cell death, wiring and circuitry formation, phagocytosis of cell debris, and synaptic pruning and sculpting of postnatal neural circuits. Moreover, microglia contribute to some neurodevelopmental disorders such as Nasu-Hakola disease (NHD), and to aged-associated neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. There is evidence that human and rodent microglia may become senescent. This event determines alterations in the microglia activation status, associated with a chronic inflammation phenotype and with the loss of neuroprotective functions that lead to a greater susceptibility to the neurodegenerative diseases of aging. In the central nervous system (CNS), Triggering Receptor Expressed on Myeloid Cells 2-DNAX activation protein 12 (TREM2-DAP12) is a signaling complex expressed exclusively in microglia. As a microglial surface receptor, TREM2 interacts with DAP12 to initiate signal transduction pathways that promote microglial cell activation, phagocytosis, and microglial cell survival. Defective TREM2-DAP12 functions play a central role in the pathogenesis of several diseases. The CX3CL1 (fractalkine)-CX3CR1 signaling represents the most important communication channel between neurons and microglia. The expression of CX3CL1 in neurons and of its receptor CX3CR1 in microglia determines a specific interaction, playing fundamental roles in the regulation of the maturation and function of these cells. Here, we review the role of the TREM2-DAP12 and CX3CL1-CX3CR1 axes in aged microglia and the involvement of these pathways in physiological CNS aging and in age-associated neurodegenerative diseases.

Suppression of homeostatic gene expression and increased expression of metabolism-related genes are early features of glaucoma in optic nerve head microglia

“…As such differential expression or manipulation of Trem2 may lead to microglial and monocyte regulatory disarray, and likely leads to differing local, temporal, and end state outcomes with increasing age and disease progression (66). TREM2 and CX3CR1 signalling both decline in aged microglia, leading to an accumulation of dystrophic and pro-inflammatory microglia in ageing (72). We have previously shown that ageing compounds gene expression changes and disease outcome in retinal ganglion cells (34), and so these gene expression changes in myeloid derived cells should be considered in the context of increasing age in addition to disease.…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…In order to perform these above‐mentioned functions a diverse array of receptors including TAM receptors, glutamate receptors, and purinergic receptors are used by microglia to efficiently communicate with other cells (Fourgeaud et al, ; York, Bernier, & MacVicar, ). Among these complex systems the CX3CL1/CX3CR1 and CD200‐CD200R axes play key roles in microglia–neuron contact (Eyo & Wu, ; Kierdorf & Prinz, ; Limatola & Ransohoff, ; Mecca, Giambanco, Donato, & Arcuri, ). Indeed, the CX3CR1 −/− mouse exhibited profound alterations in both morphology and connectivity of the mature newborn hippocampal granule neurons (Bolos et al, ).…”

Impaired Signaling of NF-κB and NRF2 in CX3CR1-Deficient Microglia: Implications in Tauopathies

“…Among these genes, polymorphisms in CX3CR1 influence disease progression but not risk in Alzheimer's disease as well as in amyotrophic lateral sclerosis, two diseases characterized by neuroinflammation (Lopez-Lopez, Gamez et al, 2014, Lopez-Lopez, Gelpi et al, 2017. CX3CR1 is the receptor for the chemokine fractalkine (CX3CL1) and is a critical signaling pathway for microglia-neuron crosstalk (Lauro, Catalano et al, 2015, Mecca, Giambanco et al, 2018. Interestingly, the CX3CL1/CX3CR1 axis is implicated in the regulation of cognitive functions and synaptic plasticity, particularly in the hippocampus.…”