Open AccessA Multifunctional Chemical Agent as an Attenuator of Amyloid Burden and Neuroinflammation in Alzheimer’s Disease
Author(s) -
HongJun Cho,
A. Sharma,
Ying Zhang,
Michael L. Gross,
Liviu M. Mirica
Publication year - 2020
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/acschemneuro.0c00114
Subject(s) - neuroinflammation , microglia , oxidative stress , amyloid (mycology) , genetically modified mouse , neurotoxicity , in vivo , chemistry , inflammation , pharmacology , amyloid beta , microbiology and biotechnology , neuroscience , medicine , transgene , biochemistry , immunology , pathology , biology , toxicity , peptide , gene
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.