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
Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Alzheimers Dement. 2025 Mar;21(3):e70023. doi: 10.1002/alz.70023.
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 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.
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.
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.
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.
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进行治疗的必要性。
我们采用了一种多模态方法，结合体内光学成像、分子技术和体外磁共振成像，来研究无记忆障碍的C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax（Tg-SwDI）小鼠的早期毛细血管功能障碍。我们还评估了碳酸酐酶抑制剂（CAIs）预防毛细血管血流紊乱的疗效。
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、黏附分子表达和淀粉样β蛋白（Aβ）负荷有关。CAI治疗改善了这些毛细血管血流紊乱，提高了氧供应，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。
在症状前阿尔茨海默病（AD）小鼠模型中发现早期毛细血管功能障碍。有证据表明AD中毛细血管停滞和功能障碍与氧输送问题有关。碳酸酐酶抑制剂在预防AD早期毛细血管血流紊乱方面的新用途。
