Astrocytes and the TGF-β1 Pathway in the Healthy and Diseased Brain: a Double-Edged Sword

Transforming growth factor betas (TGF-beta s) are known as multifunctional growth factors that participate in the regulation of key events of development, disease, and tissue repair. In the brain, TGF-beta 1 has been widely recognized as an injury-related cytokine, particularly associated with astrocyte scar formation in response to brain injury. In the last decade, however, evidence has indicated that in addition to its role in brain injury, TGF-beta 1 might be a crucial regulator of cell survival and differentiation, brain homeostasis, angiogenesis, memory formation, and neuronal plasticity. In this review, we will discuss the emerging scenario of TGF-beta 1 as a key regulator of astrocyte differentiation and function and the implications of TGF-beta 1 as a novel mediator of cellular interactions in the central nervous system. First, we will discuss the cellular and molecular basis underlying the effect of TGF-beta on astrocyte generation and its impact on angiogenesis and blood-brain barrier function. Then, we will focus on the role of astrocytes in the development and remodeling of synapses and the role of TGF-beta 1 as a new mediator of these events. Furthermore, we present seminal data that contributed to the emerging concept that astrocyte dysfunction might be associated with neurodegenerative diseases, with a special focus on Alzheimer's disease, and discuss the pros and cons of TGF-beta signaling deficits in these processes. Finally, we argue that understanding how astrocytic signals, such as TGF-beta 1, regulate brain function might offer new insights into human learning, memory, and cognition, and ultimately, this understanding may provide new targets for the treatment of neurological diseases.