Journal Article

Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis

Kura, Sreekanth, Gamallo‐Lana, Begona, Bordoni, Luca, Rasmussen, Peter Mondrup, Sakadžić, Sava, Ramos‐Cejudo, Jaime, Fruekilde, Signe K., Khatib, Mirna El, Canepa, Elisa, Fossati, Silvia, Mikkelsen, Irene Klærke, Carlsen, Jasper, Vinogradov, Sergei, Gutiérrez‐Jiménez, Eugenio, Palmfeldt, Johan, Boas, David A., Leduc‐Galindo, Desiree, Hansen, Brian, Wied, Boris, Østergaard, Leif, Mar, Adam C.

2025

Overview

INTRODUCTION Disturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimer's disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes. METHODS We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo magnetic resonance imaging, to investigate early capillary dysfunction in C57BL/6‐Tg(Thy1‐APPSwDutIowa)BWevn/Mmjax (Tg‐SwDI) mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances. RESULTS Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and amyloid beta (Aβ) load in 9‐ to 10‐month‐old Tg‐SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load. DISCUSSION These findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD. Highlights Uncovered early capillary dysfunction in a presymptomatic Alzheimer's disease (AD) mouse model. Evidence linking capillary stalls and capillary dysfunction with oxygen delivery issues in AD. Novel use of carbonic anhydrase inhibitors to prevent early capillary flow disturbances in AD.

• Publisher: John Wiley and Sons Inc
• Subject: Alzheimer Disease / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Animals / Brain - blood supply / Brain - diagnostic imaging / Brain - drug effects / Capillaries - drug effects / Capillaries - pathology / Capillaries - physiopathology / capillary dysfunction / capillary flow disturbances / capillary stalls / carbonic anhydrase inhibitors / Carbonic Anhydrase Inhibitors - pharmacology / Carbonic Anhydrase Inhibitors - therapeutic use / Cerebral Amyloid Angiopathy - drug therapy / Cerebrovascular Circulation - drug effects / Disease Models, Animal / Magnetic Resonance Imaging / Male / Mice / Mice, Inbred C57BL / Mice, Transgenic / presymptomatic