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

ABSTRACT: 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.SIGNIFICANCE STATEMENT Alzheimer's disease is characterized by progressive cognitive decline, mainly attributed to synaptotoxicity of the amyloid-? oligomers (A?Os). Here, we investigated the impact of A?Os in astrocytes, a less known subject. We show that astrocytes prevent synapse loss induced by A?Os, via production of transforming growth factor-?1 (TGF-?1). We found that A?Os trigger morphological and functional alterations in astrocytes, and impair their neuroprotective potential. Notably, TGF-?1 reduced hippocampal dendritic spine loss and memory impairment in mice that received intracerebroventricular infusions of A?Os. Our results describe a new mechanism underlying the toxicity of A?Os and indicate novel therapeutic targets for Alzheimer's disease, mainly focused on TGF-?1 and astrocytes.

SUBMITTER: Diniz LP 

PROVIDER: S-EPMC6596548 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature