Gutiérrez-Jiménez Eugenio, Rasmussen Peter Mondrup, Mikkelsen Irene Klærke, Kura Sreekanth, Fruekilde Signe K, Hansen Brian, Bordoni Luca, Carlsen Jasper, Palmfeldt Johan, Boas David A, Sakadžić Sava, Vinogradov Sergei, Khatib Mirna El, Ramos-Cejudo Jaime, Wied Boris, Leduc-Galindo Desiree, Canepa Elisa, Mar Adam C, Gamallo-Lana Begona, Fossati Silvia, Østergaard Leif
bioRxiv. 2024 Dec 9:2024.08.22.609091. doi: 10.1101/2024.08.22.609091.
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.
We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo MRI, to investigate early capillary dysfunction in Tg-SwDI mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances.
Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and Amyloid-β (Aβ) load in 9-10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load.
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.
微血管流动动力学紊乱被认为先于阿尔茨海默病（AD）的症状期出现。然而，症状前AD的证据仍然难以捉摸，这突出了针对这些早期血管变化的治疗方法的必要性。
我们采用了一种多模态方法，结合体内光学成像、分子技术和体外MRI，来研究无记忆障碍的Tg-SwDI小鼠早期的毛细血管功能障碍。我们还评估了碳酸酐酶抑制剂（CAIs）在预防毛细血管血流紊乱方面的疗效。
我们的研究发现，在9至10个月大、无记忆障碍的Tg-SwDI小鼠中，毛细血管血流紊乱与毛细血管形态改变、黏附分子表达及淀粉样β蛋白（Aβ）负荷有关。CAI治疗改善了这些毛细血管血流紊乱，增加了氧供应，并降低了Aβ负荷。
这些发现强调了毛细血管血流紊乱作为症状前AD早期生物标志物的重要性，并突出了CAIs在AD早期阶段维持血管完整性的潜力。
