Targeting the Nrf2/Amyloid-Beta Liaison in Alzheimer’s Disease: A Rational Approach

Abstract

Amyloid is a prominent feature of Alzheimer's disease (AD). Yet, a linear linkage between amyloid-β peptide (Aβ) and the disease onset and progression has recently been questioned. In this context, the crucial partnership between Aβ and Nrf2 pathways is acquiring paramount importance, offering prospects for deciphering the Aβ-centered disease network. Here, we report on a new class of antiaggregating agents rationally designed to simultaneously activate transcription-based antioxidant responses, whose lead 1 showed interesting properties in a preliminary investigation. Relying on the requirements of Aβ recognition, we identified the catechol derivative 12. In SH-SY5Y neuroblastoma cells, 12 combined remarkable free radical scavenger properties to the ability to trigger the Nrf2 pathway and induce the Nrf2-dependent defensive gene NQO1 by means of electrophilic activation of the transcriptional response. Moreover, 12 prevented the formation of cytotoxic stable oligomeric intermediates, being significantly more effective, and per se less toxic, than prototype 1. More importantly, as different chemical features were exploited to regulate Nrf2 and Aβ activities, the two pathways could be tuned independently. These findings point to compound 12 and its derivatives as promising tools for investigating the therapeutic potential of the Nrf2/Aβ cellular network, laying foundation for generating new drug leads to confront AD.

NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation

“…The cell viability of OPs exposed to compounds 1 and 2 was determined by the 3-(4,5-dimethyl thiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) assay ( Figure 7 A). Only in the case of compound 1, at 5-μM concentration, cell viability was reduced by about 20%, consistent with the previous data in SH-SY5Y cells [ 24 , 25 ].…”

“…To gain some insight on the effects of compound 1 in OP cultures, the same doses of compound 1, compound 2, curcumin, and DMF were tested for comparison. Based on the previous data obtained on SH-SY5Y cells [ 24 , 25 ], we performed the experiments with increasing concentrations (0.5, 1, and 5 µM) of the compounds. The cell viability of OPs exposed to compounds 1 and 2 was determined by the 3-(4,5-dimethyl thiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) assay ( Figure 7 A).…”

“…In this study, we demonstrate that, in OPs, the effect of curcumin on mMP is similar to the DMF effect, suggesting an electrophile-type effect. We also tested two compounds synthesized by combining the functional moieties of curcumin and diallyl sulfide [ 24 , 39 ].…”

“…To point out specificities and similarities in the effects of the two pathways and, as a future perspective, to consider these transcription factors as targets in a combined therapy aimed at treating myelin diseases, we analyzed two drugs currently used in clinical practice: pioglitazone, a PPAR-γ agonist belonging to the family of thiazolidinediones, and the NRF2 inducer dimethyl fumarate. We also tested, in our purified culture of OPs, two molecules, compounds 1 and 2, previously shown to induce the NRF2/ARE pathway in the SH-SY5Y neuroblastoma cell line [ 24 , 25 ]. They were selected from a small set of compounds synthesized by combining the hydroxycinnamoyl motif derived from curcumin and the allyl mercaptan moiety of garlic organosulfur compounds.…”

“…Compound 1 bears electrophilic features previously shown to be responsible for the activation of the NRF2. Conversely, compound 2, lacking these features, is not able to induce the NRF2 pathway ( Figure 1 ) [ 24 , 25 ]. Curcumin was also tested as the parent compound.…”