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

preprint
submitted on 19.12.2019 and posted on 23.12.2019 by Hong-Jun Cho, Anuj K. Sharma, Ying Zhang, Michael L. Gross, Liviu M. Mirica
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.

Funding

NIH R01GM114588

NIH P41GM103422

Alzheimer’s Association NIRG 12-259199

NIH P50AG05681

History

Email Address of Submitting Author

mirica@illinois.edu

Institution

University of Illinois at Urbana-Champaign

Country

United States of America

ORCID For Submitting Author

0000-0003-0584-9508

Declaration of Conflict of Interest

The authors declare no conflict of interest.

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