Astrocyte Heterogeneity: Impact to Brain Aging and Disease

Abstract

Astrocytes, one of the largest glial cell population in the central nervous system (CNS), play a key function in several events of brain development and function, such as synapse formation and function, control of neurotransmitters release and uptake, production of trophic factors and control of neuronal survival. Initially described as a homogenous population, several evidences have pointed that astrocytes are highly heterogeneous, both morphologically and functionally, within the same region, and across different brain regions. Recent findings suggest that the heterogeneity in the expression profile of proteins involved in astrocyte function may predict the selective vulnerability of brain regions to specific diseases, as well as to the age-related cognitive decline. However, the molecular mechanisms underlying these changes, either in aging as well as in brain disease are scarce. Neuroinflammation, a hallmark of several neurodegenerative diseases and aging, is reported to have a dubious impact on glial activation, as these cells release pro- and anti-inflammatory cytokines and chemokines, anti-oxidants, free radicals, and neurotrophic factors. Despite the emerging evidences supporting that reactive astrocytes have a duality in their phenotype, neurotoxic or neuroprotective properties, depending on the age and stimuli, the underlying mechanisms of their activation, cellular interplays and the impact of regional astrocyte heterogeneity are still a matter of discussion. In this review article, we will summarize recent findings on astrocyte heterogeneity and phenotypes, as well as their likely impact for the brain function during aging and neural diseases. We will focus on the molecules and mechanisms triggered by astrocyte to control synapse formation in different brain regions. Finally, we will discuss new evidences on how the modulation of astrocyte phenotype and function could impact the synaptic deficits and glial dysfunction present in aging and pathological states.

Piezo1 regulates calcium oscillations and cytokine release from astrocytes

“…Our understanding of glial cell biology and biophysics has advanced rapidly over the last two decades and it is now widely accepted that astrocytes resident in different brain regions exhibit heterogeneity in morphology and function (Matias, Morgado, & Gomes, ). Local sub‐populations of astrocytes within a common neuronal ensemble also appear to exhibit distinct functional groupings, such as the A1 and A2 phenotypes recently described (Liddelow et al, ).…”

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation

“…Given the strong AD trait associations of the M4 astrocyte/microglial metabolism module and its enrichment in AD genetic risk factors, we decided to more deeply investigate the cell type nature of this co-expression module. Astrocyte and microglia phenotypes are known to be heterogenous and dynamic, and dependent upon environmental context and stimuli 41,42 . One common categorization of astrocyte phenotypes is into deleterious pro-inflammatory "A1" astrocytes, such as the phenotype adopted in response to challenge with the pro-inflammatory molecule lipopolysaccharide (LPS), and protective "A2" astrocytes, such as the phenotype adopted after ischemic injury by middle cerebral artery occlusion 43 .…”

The frequency-dependent effect of electrical fields on the mobility of intracellular vesicles in astrocytes

“…Astrocytes are important to remove the excess of toxic waste in the CNS, maintain neurotransmitters homeostasis, regulate the extracellular space volume, transport major ions, and regulate synaptic connectivity and transmission (22)(23)(24). Particularly in the glymphatic pathway (14,15) that enables exchange between the para-arterial space and the interstitial space and allows waste products to be removed away from the arteries to the veins.…”

“…The glial astrocyte has been selected as a targeting subject to study the effect of brain waves on metabolic homeostasis and memory consolidation because, in the central nervous system (CNS) astrocytes are believed to play an important role removing excess of toxic waste, recycling neurotransmitters, and other molecules, transporting major ions, modulating neuronal excitability, and promoting synaptic remodeling (22)(23)(24)(25)(26)(27)(28). Cellular functions of astrocytes can be monitored by their activities in intracellular vesicles.…”