Aquaporin4 facilitator decreases insoluble amyloid b of 5XFAD mouse brain

Abstract

AbstractBackgroundMost brain degenerative diseases are recognized as pathologic protein accumulating diseases. To date, there have been no established treatments that promote clearance of pathological proteins. Enhancing clearance, and thus preventive reduction of accumulation of pathological proteins is an obvious target for new treatment development for this category of brain diseases. Aquaporin4 (AQP4) is one of the water channel proteins abundant in brain astrocytes, and controls excretion of metabolites from inside the brain parenchyma to the cerebrospinal fluid. It has been reported that a functional decline of AQP4 is one of the causes of intracerebral pathological protein accumulation diseases, such as amyloid‐β in Alzheimer's disease, and tau accumulation in head trauma. Therefore, promotion of AQP4 function can be expected to prevent/ameliorate intracerebral pathological protein accumulation. We administered TGN‐073, a small sized molecule that facilitates AQP4 function developed by our laboratory, to Alzheimer model 5xFAD mice and assessed its effect on Ab accumulation.Method1. Waste clearance disturbance in 5xFAD mice was assessed using the JJVCPE MRI method in 7month old 5xFAD mice and their litter mates. 2. 5xFAD mice were divided into two groups. One group received 400mg/kg TGN‐073 daily through gavage between the ages of 4 to 7months. The second group received the same volume of water. Soluble and insoluble amyloid b 40/42 was subsequently assessed in the hippocampus and cortex of these two groups.ResultTGN‐073 decreases insoluble amyloid b (Ab) 40 and Ab42 in Alzheimer transgenic mouse (5xFAD mice) brain parenchyma, whereas no significant difference was seen in the clearance of soluble Ab40 or Ab42.ConclusionWaste clearance from brain has been found to be reduced in AQP4 knockout mice and APP‐PS1 Alzheimer transgenic mice. The reduction in clearance is further found to be associated with a decrease in aquaporin 4(AQP4) function in an Alzheimer's disease model mouse. Part of Ab accumulation causation is evoked by reduced waste clearance in 5xFAD mouse. Our study shows that the AQP4 facilitator TGN‐073 prevented the insoluble Ab accumulation in 5xFAD mouse through facilitation of AQP4 activity.