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
UR - https://www.scopus.com/pages/publications/105001591191
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 -