Chronic, unresolved inflammation in brain tissue is a feature of age-related neurodegenerative conditions, and may even be the most important mechanism in these very complex conditions. The supporting cells of the brain, primarily microglia and astrocytes, become more active and inflammatory in later life. This overlaps with a rising count of senescent cells in these populations. Senescent cells produce an outsized contribution to inflammatory signaling, belying their relatively small numbers compared to non-senescent cells. Active microglia and astrocytes are largely not senescent, however. They are reacting to inflammatory signaling or molecular patterns resulting from cell dysfunction, stress, and death.
Clearing senescent cells from the brain dampens inflammation and pathology in animal models of neurodegeneration. It seems plausible that finding ways to turn off the activation of microglia and astrocytes will be similarly beneficial. In the case of microglia, the entire population can be removed without harm, allowing new non-active microglia to emerge and repopulate the brain. Astrocytes present a harder challenge, however. Given that they make up a sizable fraction of all cell in the brain, clearance really isn't an option. Some form of adjustment or reprogramming of regulatory mechanisms is called for. Fortunately, it may be the case that astrocyte activation is a consequence of microglial activation: further studies of microglial clearance as an approach to therapy may clarify this relationship.
Roles of neuropathology-associated reactive astrocytes: a systematic review
As opposed to being monolithic in function and morphology, astrocytes differ significantly depending on both tissue and cellular localization. While these characterizations have been recognized for some time, functional distinctions have only recently been investigated. Historically, in response to damage, astrocytes have been characterized as adopting a reactive phenotype. In contrast to the typically quiescent state of mature astrocytes, reactive astrocytes can become highly proliferative, and this astrogliosis is the foundation for glial scar formation.
To best support the central nervous system (CNS) in a system that can suffer from a variety of insults, astrocytes have seemingly evolved a diverse reactive response. Reactive phenotypic polarization depends on the nature of the inducing stimuli. Rather than eliciting a single response to CNS injury or insult, astrocyte reactivity is highly heterogenous. Borrowing from the nomenclature used to describe reactive macrophages and microglia, in response to tissue damage and ischemia, astrocytes adopt a neuroprotective A2 phenotype. A2s fit the traditional reactive astrocyte profile and have proliferative functions, resulting in glial scar formation, debris clearance, and blood-brain barrier (BBB) repair. They upregulate neurotrophic factors and pro-synaptic thrombospondins, thereby promoting neuronal growth and supporting synaptic repair. In contrast, neuroinflammation, infection, and aging induces a cytotoxic A1 reactive astrocyte phenotype. Neurotoxic A1 reactive astrocytes are pro-inflammatory and associated with neurodegeneration and chronic neuropathic pain, in addition to a repression of functions related to supporting neuronal survival and synaptogenesis.
The use of A1/A2 nomenclature is not universally accepted, as such a stringent dichotomy fails to accurately represent the diversity within each subset of cells. This system of classification can also give the false impression of reactive states being either entirely "helpful" or "harmful", when in reality these reactive states likely evolved to serve various functional purposes.
The environment of the aging brain can exacerbate inflammatory effects and contribute to gradual neuronal damage. During the course of normal aging, as opposed to age-associated pathologies like Alzheimer's disease, glia cells undergo a variety of physiological and functional changes. In addition to promoting neuroprotective signaling pathways, microglia in an aging brain upregulate expression of immune system response receptors, effectively becoming more sensitive to insults, and increasing production of pro-inflammatory signals. The neuroinflammatory astrocyte response in the brain that arises in advanced age is compounded by inflammation. In the absence of activated microglia cytokine secretion, age-induced astrocyte reactivity is reduced, supporting the role of activated microglia in age-associated A1-like responses.
Targeting or blocking astrocyte polarization may prove to be an effective avenue of symptom management and treatment for a host of neurodegenerative or neuroinflammatory disorders. The selective serotonin reuptake inhibitor (SSRI) Fluoxetine was found to inhibit neurotoxic astrocyte polarization upon inflammatory stimulation both in vitro and in vivo. The increased concentration of A1-associated markers in a chronic mild stress mouse model was rescued with Fluoxetine treatment. Using pharmacological inhibitors and siRNA technology, astrocytic 5HT2BR and downstream β-arrestin2 signaling were identified as the targets of the Fluoxetine-mediated inhibition of A1-like astrocyte polarization. Recently, NLY01, a GLP-1R agonist, has been investigated as a neuroprotective agent in Parkinson's disease, and was found to directly prevent microglia from inducing astrocyte polarization. These studies suggest that both current well-established therapies and those yet to be developed could be of use as neurotoxic reactive astrocyte inhibitors applicable to a wide array of neuropathologies. Continued investigation into the near-ubiquitous pathological roles of these reactive pro-inflammatory A1-like astrocytes will have important implications for how neuropathologies are studied and ultimately treated.
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