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

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

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

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 FossatiLeif Østergaard

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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.

Originalsprog	Engelsk
Artikelnummer	e70023
Tidsskrift	Alzheimer's & Dementia
Vol/bind	21
Nummer	3
ISSN	1552-5260
DOI	https://doi.org/10.1002/alz.70023
Status	Udgivet - mar. 2025

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10.1002/alz.70023

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Gutiérrez-Jiménez, E., Rasmussen, P. M., Mikkelsen, I. K., Kura, S., Fruekilde, S. K., Hansen, B., Bordoni, L., Carlsen, J., Palmfeldt, J., Boas, D. A., Sakadžić, S., Vinogradov, S., Khatib, M. E., Ramos-Cejudo, J., Wied, B., Leduc-Galindo, D., Canepa, E., Mar, A. C., Gamallo-Lana, B., ... Østergaard, L. (2025). Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis. Alzheimer's & Dementia, 21(3), Artikel e70023. https://doi.org/10.1002/alz.70023

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title = "Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis",

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.",

keywords = "Alzheimer's disease, capillary dysfunction, capillary flow disturbances, capillary stalls, carbonic anhydrase inhibitors, presymptomatic",

author = "Eugenio Guti{\'e}rrez-Jim{\'e}nez and Rasmussen, {Peter Mondrup} and Mikkelsen, {Irene Kl{\ae}rke} and Sreekanth Kura and Fruekilde, {Signe K} and Brian Hansen and Luca Bordoni and Jasper Carlsen and Johan Palmfeldt and Boas, {David A} and Sava Sakad{\v z}i{\'c} and Sergei Vinogradov and Khatib, {Mirna El} and Jaime Ramos-Cejudo and Boris Wied and Desiree Leduc-Galindo and Elisa Canepa and Mar, {Adam C} and Begona Gamallo-Lana and Silvia Fossati and Leif {\O}stergaard",

year = "2025",

month = mar,

doi = "10.1002/alz.70023",

language = "English",

volume = "21",

journal = "Alzheimer's & Dementia",

issn = "1552-5260",

publisher = "John Wiley & Sons Inc.",

number = "3",

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Gutiérrez-Jiménez, E , Rasmussen, PM , Mikkelsen, IK, Kura, S, Fruekilde, SK, Hansen, B, Bordoni, L, Carlsen, J , Palmfeldt, J, Boas, DA, Sakadžić, S, Vinogradov, S, Khatib, ME, Ramos-Cejudo, J, Wied, B, Leduc-Galindo, D, Canepa, E, Mar, AC, Gamallo-Lana, B, Fossati, S & Østergaard, L 2025, 'Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis', Alzheimer's & Dementia, bind 21, nr. 3, e70023. https://doi.org/10.1002/alz.70023

Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis. / Gutiérrez-Jiménez, Eugenio ; Rasmussen, Peter Mondrup ; Mikkelsen, Irene Klærke et al.
I: Alzheimer's & Dementia, Bind 21, Nr. 3, e70023, 03.2025.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis

AU - Gutiérrez-Jiménez, Eugenio

AU - Rasmussen, Peter Mondrup

AU - Mikkelsen, Irene Klærke

AU - Kura, Sreekanth

AU - Fruekilde, Signe K

AU - Hansen, Brian

AU - Bordoni, Luca

AU - Carlsen, Jasper

AU - Palmfeldt, Johan

AU - Boas, David A

AU - Sakadžić, Sava

AU - Vinogradov, Sergei

AU - Khatib, Mirna El

AU - Ramos-Cejudo, Jaime

AU - Wied, Boris

AU - Leduc-Galindo, Desiree

AU - Canepa, Elisa

AU - Mar, Adam C

AU - Gamallo-Lana, Begona

AU - Fossati, Silvia

AU - Østergaard, Leif

PY - 2025/3

Y1 - 2025/3

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - capillary dysfunction

KW - capillary flow disturbances

KW - capillary stalls

KW - carbonic anhydrase inhibitors

KW - presymptomatic

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U2 - 10.1002/alz.70023

DO - 10.1002/alz.70023

M3 - Journal article

C2 - 39229198

SN - 1552-5260

VL - 21

JO - Alzheimer's & Dementia

JF - Alzheimer's & Dementia

IS - 3

M1 - e70023

ER -

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

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