Astrocyte Transforming Growth Factor Beta 1 Protects Synapses against Aß Oligomers in Alzheimer's Disease Model.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, increasingly attributed to neuronal dysfunction induced by amyloid-ß oligomers (AßOs). Although the impact of AßOs on neurons has been extensively studied, only recently have the possible effects of AßOs 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 AßOs on astrocytes, and to determine whether this impact is related to the deleterious actions of AßOs on synapses. We found that AßOs 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 AßOs binding, and prevent AßO-induced synapse loss in cultured hippocampal neurons. Both a neutralizing anti-transforming growth factor-ß1 (TGF-ß1) antibody and siRNA-mediated knockdown of TGF-ß1, previously identified as an important synaptogenic factor secreted by astrocytes, abrogated the protective action of astrocyte CM against AßO-induced synapse loss. Notably, TGF-ß1 prevented hippocampal dendritic spine loss and memory impairment in mice that received an intracerebroventricular infusion of AßOs. Results suggest that astrocyte-derived TGF-ß1 is part of an endogenous mechanism that protects synapses against AßOs. By demonstrating that AßOs decrease astrocyte ability to protect synapses, our results unravel a new mechanism underlying the synaptotoxic action of AßOs in AD.SIGNIFICANCE STATEMENT Alzheimer's disease is characterized by progressive cognitive decline, mainly attributed to synaptotoxicity of the amyloid-ß oligomers (AßOs). Here, we investigated the impact of AßOs in astrocytes, a less known subject. We show that astrocytes prevent synapse loss induced by AßOs, via production of transforming growth factor-ß1 (TGF-ß1). We found that AßOs trigger morphological and functional alterations in astrocytes, and impair their neuroprotective potential. Notably, TGF-ß1 reduced hippocampal dendritic spine loss and memory impairment in mice that received intracerebroventricular infusions of AßOs. Our results describe a new mechanism underlying the toxicity of AßOs and indicate novel therapeutic targets for Alzheimer's disease, mainly focused on TGF-ß1 and astrocytes.

Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling.

The balance between excitatory and inhibitory synaptic inputs is critical for the control of brain function. Astrocytes play important role in the development and maintenance of neuronal circuitry. Whereas astrocytes-derived molecules involved in excitatory synapses are recognized, molecules and molecular mechanisms underlying astrocyte-induced inhibitory synapses remain unknown. Here, we identified transforming growth factor beta 1 (TGF-ß1), derived from human and murine astrocytes, as regulator of inhibitory synapse in vitro and in vivo. Conditioned media derived from human and murine astrocytes induce inhibitory synapse formation in cerebral cortex neurons, an event inhibited by pharmacologic and genetic manipulation of the TGF-ß pathway. TGF-ß1-induction of inhibitory synapse depends on glutamatergic activity and activation of CaM kinase II, which thus induces localization and cluster formation of the synaptic adhesion protein, Neuroligin 2, in inhibitory postsynaptic terminals. Additionally, intraventricular injection of TGF-ß1 enhanced inhibitory synapse number in the cerebral cortex. Our results identify TGF-ß1/CaMKII pathway as a novel molecular mechanism underlying astrocyte control of inhibitory synapse formation. We propose here that the balance between excitatory and inhibitory inputs might be provided by astrocyte signals, at least partly achieved via TGF-ß1 downstream pathways. Our work contributes to the understanding of the GABAergic synapse formation and may be of relevance to further the current knowledge on the mechanisms underlying the development of various neurological disorders, which commonly involve impairment of inhibitory synapse transmission.

Astrocyte-induced synaptogenesis is mediated by transforming growth factor ß signaling through modulation of D-serine levels in cerebral cortex neurons.

Assembly of synapses requires proper coordination between pre- and postsynaptic elements. Identification of cellular and molecular events in synapse formation and maintenance is a key step to understand human perception, learning, memory, and cognition. A key role for astrocytes in synapse formation and function has been proposed. Here, we show that transforming growth factor ß (TGF-ß) signaling is a novel synaptogenic pathway for cortical neurons induced by murine and human astrocytes. By combining gain and loss of function approaches, we show that TGF-ß1 induces the formation of functional synapses in mice. Further, TGF-ß1-induced synaptogenesis involves neuronal activity and secretion of the co-agonist of the NMDA receptor, D-serine. Manipulation of D-serine signaling, by either genetic or pharmacological inhibition, prevented the TGF-ß1 synaptogenic effect. Our data show a novel molecular mechanism that might impact synaptic function and emphasize the evolutionary aspect of the synaptogenic property of astrocytes, thus shedding light on new potential therapeutic targets for synaptic deficit diseases.

Neuroprotective astrocyte-derived insulin/insulin-like growth factor 1 stimulates endocytic processing and extracellular release of neuron-bound Aß oligomers.

Synaptopathy underlying memory deficits in Alzheimer's disease (AD) is increasingly thought to be instigated by toxic oligomers of the amyloid beta peptide (AßOs). Given the long latency and incomplete penetrance of AD dementia with respect to Aß pathology, we hypothesized that factors present in the CNS may physiologically protect neurons from the deleterious impact of AßOs. Here we employed physically separated neuron-astrocyte cocultures to investigate potential non-cell autonomous neuroprotective factors influencing AßO toxicity. Neurons cultivated in the absence of an astrocyte feeder layer showed abundant AßO binding to dendritic processes and associated synapse deterioration. In contrast, neurons in the presence of astrocytes showed markedly reduced AßO binding and synaptopathy. Results identified the protective factors released by astrocytes as insulin and insulin-like growth factor-1 (IGF1). The protective mechanism involved release of newly bound AßOs into the extracellular medium dependent upon trafficking that was sensitive to exosome pathway inhibitors. Delaying insulin treatment led to AßO binding that was no longer releasable. The neuroprotective potential of astrocytes was itself sensitive to chronic AßO exposure, which reduced insulin/IGF1 expression. Our findings support the idea that physiological protection against synaptotoxic AßOs can be mediated by astrocyte-derived insulin/IGF1, but that this protection itself is vulnerable to AßO buildup.

Neuron-glia signaling: Implications for astrocyte differentiation and synapse formation.

Glial cells are currently viewed as active partners of neurons in synapse formation. The close proximity of astrocytes to the synaptic cleft implicates that they strongly influence synapse function as well as suggests that these cells might be potential targets for neuronal-released molecules. In this review, we discuss the signaling pathways of astrocyte generation and the role of astrocyte-derived molecules in synapse formation in the central nervous system. Further, we discuss the role of the excitatory neurotransmitter, glutamate and transforming growth factor beta 1 (TGF-ß1) pathway in astrocyte generation and differentiation. We provide evidence that astrocytes surrounding synapses are target of neuronal activity and shed light into the role of astroglial cells into neurological disorders associated with glutamate neurotoxicity.

Glia: dos velhos conceitos às novas funções de hoje e as que ainda virão / Glia: from old concepts to new functions today and yet to come

Descritas há mais de 150 anos, as células gliais, constituintes do tecido nervoso juntamente com os neurônios, foram consideradas até pouco tempo células de suporte do cérebro, passivas e à margem do seu funcionamento. Especialmente na última década, as neurociências foram palco de uma mudança de paradigma relacionada à função e ao papel dessas células na fisiologia e patologia neurais. Neste artigo, discutimos como os avanços acerca do conhecimento sobre os astrócitos, o mais abundante tipo glial, contribuíram para o entendimento do funcionamento cerebral. Apresentamos evidências da relação entre disfunções gliais e doenças neurodegenerativas e desordens neurológicas, discutindo o potencial papel dessas células na elaboração de abordagens terapêuticas para o sistema nervoso adulto.