Sugar-linked polyphenols as inhibitors of Aβ-induced Fyn kinase activation and Tau phosphorylation in neural cells

Alzheimer’s disease (AD) is characterized by the presence of extracellular deposits of amyloid-beta (Aβ) in the brain, together with intracellular neurofibrillary tangles containing hyperphosphorylated Tau, which eventually lead to synaptic dysfunction and neuronal death. Importantly, the cellular prion protein (PrP^C), located at the neuronal cell surface, works as a high-affinity binding partner of Aβ oligomers, and the interaction between these two players results in Fyn kinase activation with subsequent Tau hyperphosphorylation. Therefore, the inhibition of Aβ-induced Fyn activation mediated by PrP^C is nowadays regarded as a promising strategy for the treatment of AD.

Inspired by 8-β-D-glucosylgenistein - a natural compound that has been shown to interact with the Aβ_1-42 peptide - this communication will focus on the synthesis and biological evaluation of a small library of sugar-linked polyphenols with neuroprotective potential. These C-glucosides were able to significantly inhibit PrP^C-dependent Aβ-induced Fyn activation and subsequent Tau phosphorylation at 10 μM in hiPSC-derived neural cells - a result that was not achieved by the natural lead molecule. The most promising C-glucosides were not neurotoxic in concentrations up to 100 μM and displayed favorable physicochemical characteristics that anticipate their ability to act in the central nervous system.

Ultimately, in this work we show, for the first time, that C-glucosyl polyphenols are able to tackle Aβ-induced Fyn kinase activation with enough efficacy to reduce Tau phosphorylation, thus having the potential to be considered for further development against AD.