Aldehyde-Mediated Neurotoxicity and Lutein Intervention: A Novel Therapeutic Strategy for Alzheimer's Disease

Alzheimer disease (AD) is a major health issue of global concern whereby there are minimal treatment options. The existing therapies, which have been recently added to the arsenal of disease-modifying anti-amyloid antibodies, provide limited clinical benefits but are characterized by a high cost and risk. This is one of the reasons why alternative approaches to address earlier, multifactorial causes of neurodegeneration are urgently required. Chronic oxidative stress is a central and early pathological alteration in AD that initiates lipid peroxidation and the production of extremely reactive and toxic α β-unsaturated aldehydes, including 4-hydroxynonenal (4-HNE) and acrolein. These aldehydes are direct mediators of neuronal injury and can result in covalent conjugates with proteins, mitochondrial dysfunction, and neuroinflammation and protein aggregation. The new, comprehensive hypothesis that has been suggested in this review is that the dietary carotenoid lutein is a high-affinity "molecular sponge" of these toxic aldehydes. In addition to its known antioxidant and anti-inflammatory effects, the conjugated polyene chain of lutein is postulated to react via a Michael addition reaction with electrophilic aldehydes, neutralizing them in the lipid-bi-layer, and avoiding their attack on other important cellular structures. We elaborate on the chemical logic of this interaction and synthesize preclinical evidence on in vitro and in vivo models of the ability of lutein to scavenge the aldehydes, reduce the pathological biomarkers, maintain the synaptic integrity and salvage the cognitive functioning. In addition, we comment on the pharmacokinetic difficulties of the brain delivery and present the future research directions, such as the formation of synthetic analogues, as well as the study of the role of lutein in the gut-brain axis. The potential to reduce the neuroprotective impact of AD in aldehyde toxicity cascade by targeting lutein is a good approach that is not only pleiotropic but also safer.