A Multifunctional Chemical Agent as an Attenuator of Amyloid Burden and Neuroinflammation in Alzheimer’s Disease

Hong-Jun Cho, Anuj K. Sharma, Ying Zhang, Michael L. Gross, Liviu M. Mirica

Research output: Contribution to journalArticlepeer-review

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 Cu2+-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.
Original languageEnglish (US)
Pages (from-to)1471-1481
Number of pages11
JournalACS Chemical Neuroscience
Volume11
Issue number10
DOIs
StatePublished - May 20 2020

Keywords

  • Alzheimer's disease
  • amyloid beta peptide
  • amyloid plaques
  • microglia activation
  • neuroinflammation
  • oxidative stress
  • p-tau
  • phosphorylated tau aggregation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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