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

Alzheimer's disease (AD) is characterized by progressive cognitive decline, increasingly attributed to neuronal dysfunction induced by amyloid-beta oligomers (A beta Os). Although the impact of A beta Os on neurons has been extensively studied, only recently have the possible effects ofA beta 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 ofA beta Os on astrocytes, and to determine whether this impact is related to the deleterious actions ofA beta Os on synapses. Wefound thatA beta 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 beta Os binding, and prevent A beta O-induced synapse loss in cultured hippocampal neurons. Both a neutralizing anti-transforming growth factor-beta 1 (TGF-beta 1) antibody and siRNA-mediated knockdown of TGF-beta 1, previously identified as an important synaptogenic factor secreted by astrocytes, abrogated the protective action of astrocyteCMagainstA beta O-induced synapse loss. Notably, TGF-beta 1 prevented hippocampal dendritic spine loss and memory impairment in mice that received an intracerebroventricular infusion of A beta Os. Results suggest that astrocyte-derived TGF-beta 1 is part of an endogenous mechanism that protects synapses against A eta Os. By demonstrating that A beta Os decrease astrocyte ability to protect synapses, our results unravel a new mechanism underlying the synaptotoxic action of A beta Os in AD.