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

Korte inhoud:INTRODUCTION: Deficiency in the aquaporin-4 (AQP4) water channel has been linked to impaired amyloid beta (A beta) 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 A beta, fibrillar deposits, and soluble A beta, while the AQP4 inhibitor caused a substantial increase in brain A beta. AQP4-facilitator treatment also reduced A beta 40 levels and A beta 40/A beta 42 ratio, whereas the inhibitor treatment increased both A beta 40 and A beta 42. Additionally, facilitator-treated mice demonstrated reduced anxiety and improved memory performance. DISCUSSION: These findings suggest that AQP4 modulation is a promising strategy to enhance A beta 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/A beta 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.

Jaar van publicatie:2025

Trefwoorden:Human medicine, Psychiatrie en neurologie

Toegankelijkheid:Open