Reactive carbonyl species (RCS) are now considered to play an important role in Alzheimer's disease (AD) pathogenesis. Indeed, methylglyoxal (MGO) or malondialdehyde (MDA) are endogenously formed during the sugar glycoxidation and lipid peroxidation of polyunsaturated fatty acids induced by oxidative stress exacerbation. Their condensation with amino groups of tissue proteins leads to AGE (Advanced Glycation Endproducts) and ALE (Advanced Lipid peroxidation Endproducts) accumulation in amyloid β (Aβ) plaques and tau-associated neurofibrillary tangles (NFT). In AD, Aβ-oligomers induce oxidative stress whereas transition metals (Zn²⁺, Cu²⁺ and Fe³⁺) stimulate Aβ aggregation and APP (amyloid precursor protein) processing. Carbonyl stress takes part in this vicious downward redox amyloid spiral leading to neurodegeneration as oxidative stress promoter and toxic mediator.^1,2 First, glycated Aβ cross-linking promotion accelerates its deposition and its protease resistance. Secondly, AGE/ALE formation not only accelerates tau hyperphosphorylation, disturbs the neuronal membrane depolarization process and the glucose transport but also exacerbates glutamate-mediated excitotoxicity. Thirdly, AGE promote oxidative stress and inflammation as well as cell apoptosis via their receptors RAGE.³
Taking into account the multifactorial pathogenesis of AD, we developed promising hybrid drugs that are simultaneously able to trap RCS (primary vicinal diamine function) as well as ROS and biometals (phenolic acid or hydroxypyridinone moiety).⁴ In the poster, synthesis of these new multifunctional AGE/ALE inhibitors and their physicochemical and biological evaluations (carbonyl trapping capacity, antioxidant activity, Cu²⁺-chelating capacity and protective properties against in vitro MGO-induced apoptosis in the model AD cell-line PC12) are reported.

We thank “SATT Nord” for financial support of this study.
References
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4. E. Lohou, N.A. Sasaki, A. Boullier and P. Sonnet, Eur. J. Med. Chem., 2016, 122, 702-722.