Abstract
Selective reuptake inhibitors (SSRIs), such as fluoxetine and sertraline, increase circulating Transforming-Growth-Factor-β1 (TGF-β1) levels in depressed patients, and are currently studied for their neuroprotective properties in Alzheimer’s disease. TGF-β1 is an anti-inflammatory cytokine that exerts neuroprotective effects against β-amyloid (Aβ)-induced neurodegeneration. In the present work, the SSRI, fluoxetine, was tested for the ability to protect cortical neurons against 1 μM oligomeric Aβ1-42-induced toxicity. At therapeutic concentrations (100 nM–1 μM), fluoxetine significantly prevented Aβ-induced toxicity in mixed glia-neuronal cultures, but not in pure neuronal cultures. Though to a lesser extent, also sertraline was neuroprotective in mixed cultures, whereas serotonin (10 nM–10 μM) did not mimick fluoxetine effects. Glia-conditioned medium collected from astrocytes challenged with fluoxetine protected pure cortical neurons against Aβ toxicity. The effect was lost in the presence of a neutralizing antibody against TGF-β1 in the conditioned medium, or when the specific inhibitor of type-1 TGF-β1 receptor, SB431542, was added to pure neuronal cultures. Accordingly, a 24 h treatment of cortical astrocytes with fluoxetine promoted the release of active TGF-β1 in the culture media through the conversion of latent TGF-β1 to mature TGF-β1. Unlike fluoxetine, both serotonin and sertraline did not stimulate the astrocyte release of active TGF-β1. We conclude that fluoxetine is neuroprotective against Aβ toxicity via a paracrine signaling mediated by TGF-β1, which does not result from a simplistic SERT blockade.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss, cognitive decline, and neuropsychiatric symptoms able to interfere with normal daily activities (Ballard et al, 2009)
Though to a lesser extent, sertraline was neuroprotective in mixed cultures only (Figure 1A), suggesting that glial cells are essential to mediate the neuroprotective effects of both fluoxetine and sertraline
SSRIs, including fluoxetine and sertraline, block the serotonin transporter (SERT) that is located on the cell bodies and terminals of 5-HT neurons, as well as on cortical astrocytes (Inazu et al, 2001)
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss, cognitive decline, and neuropsychiatric symptoms able to interfere with normal daily activities (Ballard et al, 2009). The ‘amyloid cascade hypothesis’ remains a widely accepted explanation of the etiology of AD after recent revisions (Selkoe and Hardy, 2016). The neurotoxic effects of Aβ oligomers have been investigated in vitro, with different molecular mechanisms possibly explaining these effects, such as the amplification of NMDA toxicity (Hynd et al, 2004), the loss of the canonical Wnt signaling (Caricasole et al, 2004) and the activation of cell cycle in differentiated neurons (reviewed by Herrup et al, 2004). Neurotrophic factors, which seem to be deficient in the AD brain, including Brain-derived Neurotrophic Factor (BDNF) (Castren and Tanila, 2006), Nerve Growth Factor (NGF) (Iulita et al, 2016) and Transforming-Growth-Factorβ (TGF-β1) (Wyss-Coray, 2006; Caraci et al, 2011a), have been proposed to limit the neurotoxicity of Aβ oligomers
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
