Astrocyte Transforming Growth Factor Beta 1 Protects Synapses against Aβ 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.

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

“…, 2012 ), transforming growth factor beta 1 ( Diniz et al. , 2012 , 2014 , 2017 ), thrombospondin ( Christopherson et al. , 2005 ), and d -serine ( Henneberger et al.…”

Inflammation as a central mechanism in Alzheimer's disease

“…When Aβ oligomers are injected into the hippocampus of mice, decrease in synaptic protein levels and atrophy of astrocytic processes occur. However, intracerbroventricular infusion of 10 ng TGF-β1 30 minutes before an injection of 10 pmol Aβ oligomers resulted in reduced levels of the proteins, drebrin, PSD-95, and synaptophysin, and strengthening of astrocytic processes [235] . Also, mice that were intracerebroventricularly injected with Aβ failed to spend more time with a novel object in a novel object recognition test, whereas the mice previously injected with TGF-β1 did not show memory impairments [235] .…”

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

“…Thus, release of these factors by microglia could be responsible for decreasing astrocytic synaptic engulfment. Other possible candidates for microglial-derived signals include TGFβ, which is known to reduce astrocytosis (Liddelow et al, 2017) and has also been shown to limit synapse loss following astrocyte activation (Diniz et al, 2017). Microglial derived FGF has been shown to be important for limiting astrocyte activation (Kang et al, 2014) although its specific effect on synaptic uptake by astrocytes…”