Journal
ACS CHEMICAL NEUROSCIENCE
Volume 11, Issue 10, Pages 1471-1481Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00114
Keywords
Alzheimer's disease; amyloid beta peptide; A beta; amyloid plaques; oxidative stress; phosphorylated tau aggregation; p-tau; neuroinflammation; microglia activation
Funding
- NIH [R01GM114588, P41GM103422]
- Alzheimer's Association [NIRG 12-259199]
- Washington University Knight Alzheimer's Disease Research Center [NIH P50AG05681]
- McDonnell Center for Cellular and Molecular Neurobiology at Washington University School of Medicine
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Alzheimer's disease (AD) is the most common neurodegenerative disease, and its main hallmark is the deposition of amyloid beta (A beta) peptides. However, several clinical trials focusing on A beta-targeting agents have failed recently, and thus new therapeutic leads are focusing on alternate targets such as tau protein pathology, A beta-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 A beta-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 Cu2+-induced A beta neurotoxicity. Along with demonstrating in vivo A beta-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 A beta-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.
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