Psychological Stress as a Risk Factor for Accelerated Cellular Aging and Cognitive Decline: The Involvement of Microglia-Neuron Crosstalk

Abstract

The relationship between the central nervous system (CNS) and microglia is lifelong. Microglia originate in the embryonic yolk sac during development and populate the CNS before the blood-brain barrier forms. In the CNS, they constitute a self-renewing population. Although they represent up to 10% of all brain cells, we are only beginning to understand how much brain homeostasis relies on their physiological functions. Often compared to a double-edged sword, microglia hold the potential to exert neuroprotective roles that can also exacerbate neurodegeneration once compromised. Microglia can promote synaptic growth in addition to eliminating synapses that are less active. Synaptic loss, which is considered one of the best pathological correlates of cognitive decline, is a distinctive feature of major depressive disorder (MDD) and cognitive aging. Long-term psychological stress accelerates cellular aging and predisposes to various diseases, including MDD, and cognitive decline. Among the underlying mechanisms, stress-induced neuroinflammation alters microglial interactions with the surrounding parenchymal cells and exacerbates oxidative burden and cellular damage, hence inducing changes in microglia and neurons typical of cognitive aging. Focusing on microglial interactions with neurons and their synapses, this review discusses the disrupted communication between these cells, notably involving fractalkine signaling and the triggering receptor expressed on myeloid cells (TREM). Overall, chronic stress emerges as a key player in cellular aging by altering the microglial sensome, notably via fractalkine signaling deficiency. To study cellular aging, novel positron emission tomography radiotracers for TREM and the purinergic family of receptors show interest for human study.

Keywords: chronic psychological stress; cognitive aging; major depressive disorder; microglia; neuron; oxidative stress; synapse.

FIGURE 1

Psychological stress and inflammation alter microglia-neuron communication and lead to cellular aging. Psychological stress induces brain inflammation and oxidative stress resulting in cellular aging when prolonged. This hostile brain environment disrupts the microglia-neuron brain communication and leads to cognitive decline. The top panel illustrates two major types of stress lived by humans. The middle panel shows the different microglia-neuron signaling pathways in the brain and the key inflammatory factors identified in chronic stress. The bottom panel illustrates the different cellular aging processes happening when cells undergo cellular aging, which is often associated with inflammation and aging.

FIGURE 2

Microglial study using PET in stress and aging. PET is a widely used technique when investigating microglial activity in pathology. In the top left, microglial labeling of radiotracers is quantified to provide insight into their function in the human brain in a non-invasive manner. In the top right a myriad of tracers provide different information on the function of microglia in the brain. The bottom left panel highlights some of the cognitive deficits observed in aging that can be accelerated with chronic stress. The bottom right panel illustrates the key regions and deficits associated with stress and aging.