Lipophenol compounds as new hybrid tools against oxidative and carbonyl stress in Alzheimer’s disease

Alzheimer’s disease (AD) accounts for 80% of dementia cases worldwide. The major histopathological marker is the presence of extracellular senile plaques composed of beta amyloid peptide aggregates. Beta amyloid peptide accumulation leads to oxidative stress, which through lipid peroxidation induces the formation of reactive carbonyl species (small aldehydes as malondialdehyde, glyoxal or acrolein). These compounds are responsible for carbonyl stress as they form adducts with proteins, lipids and nucleic acids and disturb their functions. Oxidative and carbonyl stress (COS) are thereby therapeutics targets to fight AD progression.Polyphenols and omega-3 polyunsaturated fatty acids (PUFAs) are two types of natural compounds known to reduce COS. However, their efficacy in vivo is limited by the low bioavailability of polyphenols and the oxidation susceptibility of PUFAs. Lipophenols are hybrid molecules that have been designed to counteract COS. They associate a polyphenol, a PUFA (docosahexaenoic acid (DHA)), and a nucleophile alkyl group. In previous studies, lipophenols showed ability to reduce COS in both in vitro and in vivo models of age-related macular degeneration.In this work, an in vitro methodology was developed to evaluate the potential of three lipophenols to reduce COS in a human neuroblastoma cell line, using acrolein as carbonyl stressor. Quercetin-7-isopropyl-3-DHA showed the best protection against toxic concentrations of acrolein and was selected for further in vivo assays to evaluate its therapeutic potential in a transgenic mouse model of AD. To produce a sufficient amount of quercetin-7-IP-3-DHA for in vivo evaluation, a new methodology was developed using a chemoenzymatic pathway.