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

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.