Astrocytic MicroRNA in Ageing, Inflammation, and Neurodegenerative Disease

Abstract

Astrocytes actively regulate numerous cell types both within and outside of the central nervous system in health and disease. Indeed, astrocyte morphology, gene expression and function, alongside the content of astrocyte-derived extracellular vesicles (ADEVs), is significantly altered by ageing, inflammatory processes and in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Here, we review the relevant emerging literature focussed on perturbation in expression of microRNA (miRNA), small non-coding RNAs that potently regulate gene expression. Synthesis of this literature shows that ageing-related processes, neurodegenerative disease-associated mutations or peptides and cytokines induce dysregulated expression of miRNA in astrocytes and in some cases can lead to selective incorporation of miRNA into ADEVs. Analysis of the miRNA targets shows that the resulting downstream consequences of alterations to levels of miRNA include release of cytokines, chronic activation of the immune response, increased apoptosis, and compromised cellular functioning of both astrocytes and ADEV-ingesting cells. We conclude that perturbation of these functions likely exacerbates mechanisms leading to neuropathology and ultimately contributes to the cognitive or motor symptoms of neurodegenerative diseases. This field requires comprehensive miRNA expression profiling of both astrocytes and ADEVs to fully understand the effect of perturbed astrocytic miRNA expression in ageing and neurodegenerative disease.

Keywords: Alzheimer’s disease; Parkinson’s disease; ageing; amyotrophic lateral sclerosis; astrocytes; inflammation; microRNA; neurodegeneration.

FIGURE 1

Altered expression of miRNA in astrocytes (A) and astrocyte-derived extracellular vesicles (ADEVs) (B), arising from neurodegenerative, inflammatory, and ageing processes, contributes to sustained central nervous system (CNS) inflammation, neuronal injury, dysregulated autophagy, and mitochondrial dysfunction in astrocytes and neurons, and increased apoptosis. Uptake of ADEVs by neurons and other cell types is suggested to have numerous downstream effects. Together, these insults can exacerbate CNS pathology and contribute to the cognitive and motor symptoms observed in neurodegenerative conditions, indicating that dysregulated expression of astrocytic miRNA plays a central role in neurodegenerative disease. Alternatively, anti-inflammatory effects are observed in response to certain stimuli. Red font and dashed red arrows denote postulated links.