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

Gutierrez-Jimenez, E.; Rasmussen, P. M.; Mikkelsen, I. K.; Kura, S.; Fruekilde, S. K.; Hansen, B.; Bordoni, L.; Carlsen, J.; Palmfeldt, J.; Boas, D. A.; Sakadzic, S.; Vinogradov, S. A.; El Khatib, M.; Ramos-Cejudo, J.; Wied, B.; Leduc-Galindo, D.; Canepa, E.; Mar, A. C.; Gamallo-Lana, B.; Fossati, S.; Ostergaard, L.

doi:10.1101/2024.08.22.609091

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bioRxiv · 10.1101/2024.08.22.609091

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

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Abstract

Structured abstractO_ST_ABSINTRODUCTIONC_ST_ABSDisturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimers disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes. METHODSWe 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. RESULTSOur study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and Amyloid-{beta} (A{beta}) load in 9-10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced A{beta} load. DISCUSSIONThese 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.

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Gutierrez-Jimenez, E., Rasmussen, P. M., Mikkelsen, I. K., Kura, S., Fruekilde, S. K., Hansen, B., Bordoni, L., Carlsen, J., Palmfeldt, J., Boas, D. A., Sakadzic, S., Vinogradov, S. A., El Khatib, M., Ramos-Cejudo, J., Wied, B., Leduc-Galindo, D., Canepa, E., Mar, A. C., Gamallo-Lana, B., Fossati, S., Ostergaard, L.. 2024-08-22. Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis. https://doi.org/10.1101/2024.08.22.609091

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