Abstract
Alzheimer's disease (AD) is the most common neurodegenerative 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, L1 [4-(benzo[d]thiazol-2-yl)-2-((4,7-dimethyl-1,4,7-triazonan-1-yl)methyl)-6-methoxyphenol], that integrates Aβ-interacting and metal-binding fragments in a single molecular framework, exhibits significant antioxidant activity and metal chelating ability, and also rescues neuroblastoma N2A cells from Cu(2+)-induced Aβ neurotoxicity. Along with demonstrating in vivo Aβ-binding and favorable brain uptake properties, L1 treatment of transgenic 5xFAD mice 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. Moreover, L1 mitigates the neuroinflammatory response of the activated microglia during the Aβ-induced inflammation process. Overall, these multifunctional properties of L1 to attenuate the formation of amyloid plaques and associated p-tau aggregates while also reducing the microglia-mediated neuroinflammatory response are 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.