Mechanism of anti-AD action of OAB-14 by enhancing the function of glymphatic system

Xian Zhang; Ruolin Cao; Chao Zhu; Luxi Yang; Na Zheng; Wenshuang Ji; Peng Liu; Tianyan Chi; Xuefei Ji; Zhonghui Zheng; Guoliang Chen; Libo Zou

doi:10.1016/j.neuint.2023.105633

Mechanism of anti-AD action of OAB-14 by enhancing the function of glymphatic system

Neurochem Int. 2023 Oct 27:105633. doi: 10.1016/j.neuint.2023.105633. Online ahead of print.

Authors

Xian Zhang¹, Ruolin Cao², Chao Zhu³, Luxi Yang⁴, Na Zheng⁵, Wenshuang Ji⁶, Peng Liu⁷, Tianyan Chi⁸, Xuefei Ji⁹, Zhonghui Zheng¹⁰, Guoliang Chen¹¹, Libo Zou¹²

Affiliations

¹ Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
² Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
³ Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
⁴ Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
⁵ Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
⁶ Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
⁷ Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
⁸ Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
⁹ Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
¹⁰ Shandong Xinhua Pharmaceutical Co., Ltd., Zibo, Shandong, 255086, PR China. Electronic address: [email protected].
¹¹ Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
¹² Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].

PMID: 39491236
DOI: 10.1016/j.neuint.2023.105633

Abstract

The number of patients with Alzheimer's disease is increasing year by year, but only a few medications are available. We found that OAB-14, a new small molecule, can improve cognitive deficits in various mouse AD models. The structure and mechanism of OAB-14 are distinct from anti-AD medications that have been unsuccessful in recent clinical trials. OAB-14 can effectively reduce the accumulation of Aβ in the brain, but has no inhibitory effect on Aβ production enzymes. Reportedly, Aβ can be drained into the systemic circulation to be metabolized through the glymphatic system and meningeal lymphatic vessels. Our research has shown that OAB-14 is capable of enhancing the glymphatic system function by promoting the influx and efflux of the CSF tracers to the brain and deep cervical lymph nodes, respectively. After blocking the central lymphatic drainage, the effect of OAB-14 in improving cognitive impairments disappeared. Furthermore, OAB-14 may up-regulate AQP4 expression by acting on PPARγ-P2X7r-AQP4 pathway and protect the polarity of AQP4 by upregulating the expression of SNTA1, Agrin, and Abca1, which are closely associated with the proper functioning of the glymphatic system. In summary, OAB-14 can promote the clearance of brain Aβ through the glymphatic system and improve cognitive impairment.

Keywords: Alzheimer's disease; Aquaporin-4; Glymphatic system; OAB-14; β-Amyloid.