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.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, increasingly attributed to neuronal dysfunction induced by amyloid-␤ oligomers (A␤Os). Although the impact of A␤Os on neurons has been extensively studied, only recently have the possible effects of A␤Os on astrocytes begun to be investigated. Given the key roles of astrocytes in synapse formation, plasticity, and function, we sought to investigate the impact of A␤Os on astrocytes, and to determine whether this impact is related to the deleterious actions of A␤Os on synapses. We found that A␤Os interact with astrocytes, cause astrocyte activation and trigger abnormal generation of reactive oxygen species, which is accompanied by impairment of astrocyte neuroprotective potential in vitro. We further show that both murine and human astrocyte conditioned media (CM) increase synapse density, reduce A␤Os binding, and prevent A␤O-induced synapse loss in cultured hippocampal neurons. Both a neutralizing anti-transforming growth factor-␤1 (TGF-␤1) antibody and siRNA-mediated knockdown of TGF-␤1, previously identified as an important synaptogenic factor secreted by astrocytes, abrogated the protective action of astrocyte CM against A␤O-induced synapse loss. Notably, TGF-␤1 prevented hippocampal dendritic spine loss and memory impairment in mice that received an intracerebroventricular infusion of A␤Os. Results suggest that astrocyte-derived TGF-␤1 is part of an endogenous mechanism that protects synapses against A␤Os. By demonstrating that A␤Os decrease astrocyte ability to protect synapses, our results unravel a new mechanism underlying the synaptotoxic action of A␤Os in AD.

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