Alzheimer’s disease (AD) is the most common neurodegenerative degenerative disease, and its main hallmark is the deposition of amyloid beta (Aβ) peptides. However, several clinical trials focusing on Aβ-targeting agents have failed recently, and thus new therapeutic leads are focusing on alternate targets such as tau protein pathology, Aβ-metal induced oxidative stress, and neuroinflammation. To address these different pathological aspects of AD, we have employed a multifunctional compound (MFC) L1 that integrates Aβ-interacting and metal-binding functional groups in a single molecular framework. By perturbing the interactions between the Aβ species and metal ions during the Aβ aggregation process, L1 alleviates the formation of neurotoxic Aβ oligomers and promotes the formation of nontoxic, amorphous Aβ aggregates. Furthermore, the significant antioxidant activity and strong metal chelating ability of L1 are operating cooperatively to rescue neuroblastoma N2A cells from Cu2+-induced Aβ neurotoxicity. Along with in vivo Aβ-binding and favorable BBB permeability properties, the treatment of transgenic 5xFAD mice with L1 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates in the brain by 40–50% versus the vehicle-treated 5xFAD mice. Besides, L1 mitigates the neuroinflammatory response of the activated microglia during the Aβ-induced inflammation process. Overall, these results suggest that L1 not only efficiently attenuates the formation of amyloid plaques and p-tau aggregates in vivo, but also reduces the microgliamediated neuroinflammatory response, which is quite uncommon among the previously reported amyloid-targeting chemical agents, and thus L1 could be envisioned as a lead compound for the development of novel AD therapeutics.
InstitutionUniversity of Illinois at Urbana-Champaign
CountryUnited States of America
ORCID For Submitting Author0000-0003-0584-9508
Declaration of Conflict of InterestThe authors declare no conflict of interest.