Targeting Alzheimer's disease hallmarks with the Nrf2 activator Isoeugenol

Alzheimer´s disease is a neurodegenerative disease and the most common cause of dementia with no cure or treatment. Therefore, the investigation to find a disease-modifying therapeutic is crucial. From a pathophysiological point of view, AD is characterized by the loss of homeostatic functions that control redox and energy metabolism, neuroinflammation, and proteostasis. The transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) is a master controller of these functions and, in the past decades, recent reports have shown that its overall activity is compromised in AD. Thus, Nrf2 has been considered an attractive molecular target for AD therapeutic research. Most pharmacological Nrf2 activators are small electrophilic molecules that react with cysteine residues present in Kelch-like ECH-Associating protein 1 (Keap1), thereby inducing Nrf2 release and further nuclear translocation and activation. Accordingly, low molecular weight skin allergens, such as dimethyl fumarate, currently used to treat the relapsing forms of multiple sclerosis and with positive results in preventing spatial memory impairments and hippocampal neurodegeneration in rats, are able to activate Nrf2. This activation is well explained by their direct reactivity towards key cysteine residues of Keap1, leading to its dissociation from Nrf2, which in turn is translocated to the nucleus inducing the transcription of over 250 protective genes. Hence, we conducted a ground-breaking study where the potential of Isoeugenol, a skin allergen with electrophilic properties, to activate Nrf2 and revert some AD hallmarks, was investigated. This work was conducted in vitro (in mice microglia cells exposed to LPS and neuronal cells overexpressing the human APP with Swedish mutation, N2a-APPswe) and in vivo (in the AD double transgenic mice, APP/PS1, intranasally administered with Isoeugenol), at an early (6-month-old animals) and late (11-month-old animals) AD stage. Overall, the results showed that Isoeugenol exhibit a good pharmacokinetic and pharmacodynamic profile. Isoeugenol activates Nrf2 and displays antioxidant and anti-inflammatory effects and reduced the levels of Aβ peptides in in vitro and in vivo models of AD. In addition, its positive effect on metabolism was also demonstrated in vivo, as it reduced the triglyceride and LDL cholesterol levels in treated AD mice. Importantly, Isoeugenol improved the memory deficits observed in APP/PS1 mice, which was more evident in older animals (11-month-old), reinforcing its potential in ameliorating AD hallmarks, even at a late stage.