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

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-03-25 DOI:10.1002/alz.70023

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

{"title":"Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis","authors":"Eugenio Gutiérrez-Jiménez, Peter Mondrup Rasmussen, Irene Klærke Mikkelsen, Sreekanth Kura, Signe K. Fruekilde, Brian Hansen, Luca Bordoni, Jasper Carlsen, Johan Palmfeldt, David A. Boas, Sava Sakadžić, Sergei Vinogradov, Mirna El Khatib, Jaime Ramos-Cejudo, Boris Wied, Desiree Leduc-Galindo, Elisa Canepa, Adam C. Mar, Begona Gamallo-Lana, Silvia Fossati, Leif Østergaard","doi":"10.1002/alz.70023","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Uncovered early capillary dysfunction in a presymptomatic Alzheimer's disease (AD) mouse model.</li>\n \n <li>Evidence linking capillary stalls and capillary dysfunction with oxygen delivery issues in AD.</li>\n \n <li>Novel use of carbonic anhydrase inhibitors to prevent early capillary flow disturbances in AD.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0000,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70023","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's & Dementia","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/alz.70023","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

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.

Abstract Image

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.