Aquaporin 4 modulation drives amyloid burden and cognitive abilities in an APPPS1 mouse model of Alzheimer's disease.

INTRODUCTION

Deficiency in the aquaporin-4 (AQP4) water channel has been linked to impaired amyloid beta (Aβ) clearance. However, a detailed morphopathological analysis of amyloid deposition following AQP4 therapeutic modulation remains unexplored.

METHODS

Two-month-old amyloid precursor protein presenilin 1 (APPPS1) mice were treated daily for 28 days with either the AQP4 facilitator N-(3-(Benzyloxy)pyridin-2-yl) benzene-sulfonamide (TGN-073) or the AQP4 inhibitor N-(1,3,4-thiadiazol-2-yl)pyridine-3-carboxamide dihydrochloride (TGN-020) (both at 200 mg/kg). Controls included vehicle-treated APPPS1 and WT C57BL/6J mice. Comprehensive histopathological, biochemical, and behavioral analyses were conducted.

RESULTS

Mice treated with AQP4 facilitator showed a significant reduction in total Aβ, fibrillar deposits, and soluble Aβ, while the AQP4 inhibitor caused a substantial increase in brain Aβ. AQP4-facilitator treatment also reduced Aβ40 levels and Aβ40/Aβ42 ratio, whereas the inhibitor treatment increased both Aβ40 and Aβ42. Additionally, facilitator-treated mice demonstrated reduced anxiety and improved memory performance.

DISCUSSION

These findings suggest that AQP4 modulation is a promising strategy to enhance Aβ clearance and a potential therapeutic target in Alzheimer's disease.

HIGHLIGHTS

Intramural periarterial drainage of the interstitial fluid mediated by aquaporin-4 (AQP4) is a key element that ensures clearance of catabolites/Aβ peptide from within the brain parenchyma. Inhibition of AQP4 in an APPPS1 mouse model of AD leads to increased amyloid deposition and deficient behavior compared to untreated transgenic animals. Pharmaceutical facilitation of AQP4 in the same APPPS1 mouse model leads to a massive decrease in amyloid burden and improves the behavioral performance of the animals compared to untreated control APPPS1 mice.