Microglia Phenotypes in Aging and Neurodegenerative Diseases

Abstract

Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development. This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

Inflammasome activation in traumatic brain injury and Alzheimer's disease

“…However, recent research has shown that these traditional phenotypic classifications of microglia are not all inclusive, and alternative and intermediate forms may exist [31,34]. Studies investigating microglia activation after CNS injury or illness have noted that the M1/M2 microglial classification is simplistic, as multipurpose and alternative forms have been identified after injury [37,38]. For example, the anti-inflammatory and regenerative M2 form has been further subdivided into M2a, M2b, M2c [33,39,40] and M2d subtypes [38,41].…”

“…Studies investigating microglia activation after CNS injury or illness have noted that the M1/M2 microglial classification is simplistic, as multipurpose and alternative forms have been identified after injury [37,38]. For example, the anti-inflammatory and regenerative M2 form has been further subdivided into M2a, M2b, M2c [33,39,40] and M2d subtypes [38,41]. The M2a form is activated by IL-4 and IL-13 and plays a role in anti-parasitic responses in that it increases scavenger receptors and induces phagocytosis, IL-10 secretion, and tissue growth and repair [33,39,41].…”

Microglia-mediated neuroinflammation and neuroplasticity after stroke

“…Several immunogenic types with inflammatory and interferon-responsive profiles persist throughout the lifespan and increase with time (Hammond et al, 2019 ). Senescent microglia, referred to as “primed microglia,” are hypersensitive to neurotoxic and inflammatory insults, and they express high levels of pro-inflammatory mediators and reactive species, while showing deficits in phagocytosis and motility (Buga et al, 2013 ; Rawji et al, 2016 ; Wendimu and Hooks, 2022 ). Age exacerbates white matter damage, deteriorates functional outcomes and increases the severity of secondary neurodegeneration after stroke (Suenaga et al, 2015 ; Kluge et al, 2018 ).…”

Prenylation Defects and Oxidative Stress Trigger the Main Consequences of Neuroinflammation Linked to Mevalonate Pathway Deregulation

“…An imbalance of these microglial functions may trigger the onset or exacerbation of neurodegeneration, a severe and debilitating neuroinflammatory disease that may occur as a result of specific and persistent stimuli, with progressive degeneration and death of neurons. All of this is because of microglia cells, which could also damage and kill neurons, depending on the type of inflammatory response, resulting in psychomotor damage, which characterizes the phenotype of neurodegenerative diseases [ 79 ]. Noteworthy, MKD syndromes are characterized, among the other clinical features, by recurrent episodes of fever, one of the clinical signs that unites autoinflammatory diseases with other inflammatory symptoms and neurological involvement especially in the most severe forms (mental and psychomotor retardation, progressive cerebellar ataxia, visual impairment, epilepsy) [ 6 ].…”