Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease

Abstract

Recent epidemiological evidence demonstrated that diabetes is a risk factor for AD onset and development. Indeed, meta-analyses of longitudinal epidemiologic studies show that diabetes increases AD risk by 50-100%, being insulin resistance (IR) the main binding link between diabetes and AD. Astrocytes are the foremost cerebral macroglial cells and are responsible for converting glucose into lactate and transfer it to neurons that use it as fuel, but Aβ(1-42) impairs insulin signaling and glycogen storage. Recent prospective studies showed that the Mediterranean diet is associated with lower incidence of AD. We hypothesized that hydroxytyrosol (HT, the preeminent polyphenol of olives and olive oil) could exert beneficial effects on IR associated with AD and investigated it mechanisms of action in an astrocytic model of AD. The astrocytic cell line C6 was exposed to Aβ(25-35) and co-incubated with HT for different periods. After treatment with Aβ(25-35), astrocytes' viability was significantly decreased as compared with controls; however, both pre- and post-treatment with HT prevented this effect. Mechanistically, we found that the preventive role of HT on Aβ(25-35)- induced cytotoxicity in astrocytes is moderated by an increased HT-induced activation of Akt, which is mediated by the insulin signaling pathway. In addition, we report that HT prevented the pronounced activation of mTOR, thereby restoring proper insulin signaling. In conclusion, we demonstrate that HT protects Aβ(25-35)-treated astrocytes by improving insulin sensitivity and restoring proper insulin-signaling. These data provide some mechanistic insight on the observed inverse association between olive oil consumption and prevalence of cognitive impairment. © 2017 BioFactors, 43(4):540-548, 2017.

Pharma-Nutritional Properties of Olive Oil Phenols. Transfer of New Findings to Human Nutrition

“…Even though these association might be casual, some ad hoc studies with olive biophenols are being undertaken. One example is that of HT, which was able to restore proper insulin signaling in an in vitro model of Alzheimer’s disease (AD) [ 27 ]. It is also noteworthy that Qosa et al tested the effects of EVOO [ 28 ] and of oleocanthal (OC) [ 29 ] in a transgenic mouse model of AD.…”

“…Recent studies have supported the protective capacities of HT and Tyr through the reduction in inflammatory markers, downregulation of apoptotic proteins, and ameliorated mitochondrial dysfunction [ 136 , 137 , 138 , 139 ]. In this sense, both pre- and post-treatment with HT prevented Aβ(25–35)-induced astrocytic cell line C6 cytotoxicity, induced Akt activation, and reduced the activation of mTOR, leading to improved insulin sensitivity and restoration of proper insulin-signaling [ 27 ].…”

Comparison of the anti-angiogenic potential of hydroxytyrosol and five derivatives

“…2 In the last years, scientific evidence has accumulated pointing to the pleiotropic effects of HT on multiple targets. In fact, demonstrated beneficial effects of HT for human health include its antidiabetic, 3,4 antifungal, 5 antiinflammatory, 6 antiparasitic, 7 cardio- 8 and neuroprotective 9 activities. HT has also beneficial effects on metabolic syndrome 10 and antitumoral effects of HT have been reported.…”

Bioactivity of Olive Oil Phenols in Neuroprotection

“…It has recently evidenced that diabetes is a risk factor for AD onset and development, being insulin resistance the main link between diabetes and AD. In this context, Crespo et al [ 146 ] demonstrated that hydroxytyrosol exerts beneficial effects on insulin resistance associated with AD in an astrocytic model of AD. Pre- and post-treatment with hydroxytyrosol counteracted cell death induced by Aβ(25–35) through the activation of Akt.…”