Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid-ß (Aß) oligomers.

BACKGROUND AND PURPOSE: Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio-1911 in Aß oligomer (AßO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). EXPERIMENTAL APPROACH: Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AßO. KEY RESULTS: LASSBio-1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AßO-triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio-1911 improves behavioural performance and rescues synaptic and memory function in AßO-infused mice. CONCLUSION AND IMPLICATIONS: These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD.

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.