Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

Abstract

The single largest risk factor for etiology of neurodegenerative diseases like Alzheimer’s disease is increased age. Therefore, understanding the changes that occur as a result of aging is central to any possible prevention or cure for such conditions. Microglia, the resident brain glial population most associated with both protection of neurons in health and their destruction is disease, could be a significant player in age related changes. Microglia can adopt an aberrant phenotype sometimes referred to either as dystrophic or senescent. While aged microglia have been frequently identified in neurodegenerative diseases such as Alzheimer’s disease, there is no conclusive evidence that proves a causal role. This has been hampered by a lack of models of aged microglia. We have recently generated a model of senescent microglia based on the observation that all dystrophic microglia show iron overload. Iron‐overloading cultured microglia causes them to take on a senescent phenotype and can cause changes in models of neurodegeneration similar to those observed in patients. This review considers how this model could be used to determine the role of senescent microglia in neurodegenerative diseases.

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…Microglial M1 pro-inflammatory status, as measured by the number of IBA1-and CD68-positive cells, was reduced following DMF treatment in hypoperfused mice [123], in OGD-stressed rats [124], LPS-treated mice, vertebral hypoxic ischemia in mice [125], EAE mice [126], the mouse MPTP model of PD [127], rumpshaker hypomyelination mice [128], after spinal cord injury (SCI) in mice [129], ICH in mice [130] and in wild-type mice [131] as well as in mouse primary microglia cultures [132]. Interestingly, DMF increased the number of cluster of differentiation 86 (CD86)-positive microglia in aged rats with streptozotocin-induced AD [133], possibly due to altered inflammatory signaling in aged compared to non-aged microglia [7]. Levels of M2 microglia phenotype markers, such as MRC1/CD206, resistin-like alpha (RETNLA) and ARG1, were elevated by the addition of DMF to (activated) primary microglia cultures [134,135].…”

“…For quite some time, the dysregulation of the peripheral immune system, causing immune cells infiltrating the CNS, autoreactivity against myelin sheath components and secondary BBB dysfunction, has been considered to be the primary cause of MS CNS pathology, defined as the outside-in hypothesis [ 5 ]. However, more recent research on MS and other neurodegenerative diseases has indicated a central role for a distinct type of macrophage found in the CNS, the microglia [ 6 , 7 ]. The hypothesis in which MS pathology is first and foremost caused by CNS-intrinsic factors, subsequently leading to the infiltration of peripheral immune cells via a leaking BBB, represents the inside-out model [ 8 , 9 ], which is supported by pathological evidence showing the absence of peripheral immune cells in newly forming MS lesions [ 10 ].…”

The Role of Microglia in Perioperative Neurocognitive Disorders

“…The proinflammatory cytokines such as TNF-α and IL-1β released from hippocampal microglia isolated from aged rats following stimulation with lipopolysaccharide was significantly higher in comparison with young rats (Kawano et al, 2015). The shift of aged microglia tends to the proinflammatory' phenotypes (termed microglial priming) and may reflect an increase in inflammation associated with aging (Luo et al, 2010;Angelova and Brown, 2019). A recent study demonstrated that the hippocampal expression of SIRT1, which is associated with inflammation, decreased with age, resulting in microglial activation and increased proinflammatory cytokines in the hippocampus of aged rats.…”

Chloroquine, the Coronavirus Crisis, and Neurodegeneration: A Perspective

“…Recent studies suggest that this may also involve deleterious reactive transformation in astrocytes (44). Notably, elimination of senescent glial cells, which are known to release proinflammatory modulators, is beneficial (45)(46)(47).…”