Cerebral proteome adaptations to amyloid angiopathy are prevented by carbonic anhydrase inhibitors

TY - JOUR

T1 - Cerebral proteome adaptations to amyloid angiopathy are prevented by carbonic anhydrase inhibitors

AU - Carlsen, Jasper

AU - Fossati, Silvia

AU - Østergaard, Leif

AU - Gutiérrez-Jiménez, Eugenio

AU - Palmfeldt, Johan

N1 - Publisher Copyright: © 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

PY - 2025/4

Y1 - 2025/4

N2 - BACKGROUND: Cerebral amyloid angiopathy (CAA) is a hallmark of Alzheimer's disease (AD), linked to adverse effects of emerging AD treatments. We explored the molecular effects of CAA in mouse brain and evaluated how these could be prevented by two repurposed United States Food and Drug Administration (FDA) approved treatments. METHODS: Brain proteomics was performed on the Tg-SwDI genetic mouse model carrying disease causing mutations and developing AD characteristic cognitive deficits and severe CAA. Cortical and hippocampal tissues from presymptomatic male and female mice were studied. RESULTS: We identify a core of dysregulated proteins across studies, including established markers of AD as well as proteins indicative of astrogliosis and negative regulators of synaptic stability and function. Two FDA approved, repurposed carbonic anhydrase inhibitors (CAIs), acetazolamide and methazolamide, were effective in preventing these molecular adaptations. DISCUSSION: The two drugs broadly prevent proteome adaptations to the detrimental genotype and retain glutamatergic synapse proteins significantly closer to wild-type levels. Highlights: The brain proteome changes of mice with CAA are mapped. Cortical and hippocampal tissues from presymptomatic male and female mice are studied. Markers of AD, astrogliosis, and synaptic stability are dysregulated. Two CAI are effective in preventing these protein changes.

AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) is a hallmark of Alzheimer's disease (AD), linked to adverse effects of emerging AD treatments. We explored the molecular effects of CAA in mouse brain and evaluated how these could be prevented by two repurposed United States Food and Drug Administration (FDA) approved treatments. METHODS: Brain proteomics was performed on the Tg-SwDI genetic mouse model carrying disease causing mutations and developing AD characteristic cognitive deficits and severe CAA. Cortical and hippocampal tissues from presymptomatic male and female mice were studied. RESULTS: We identify a core of dysregulated proteins across studies, including established markers of AD as well as proteins indicative of astrogliosis and negative regulators of synaptic stability and function. Two FDA approved, repurposed carbonic anhydrase inhibitors (CAIs), acetazolamide and methazolamide, were effective in preventing these molecular adaptations. DISCUSSION: The two drugs broadly prevent proteome adaptations to the detrimental genotype and retain glutamatergic synapse proteins significantly closer to wild-type levels. Highlights: The brain proteome changes of mice with CAA are mapped. Cortical and hippocampal tissues from presymptomatic male and female mice are studied. Markers of AD, astrogliosis, and synaptic stability are dysregulated. Two CAI are effective in preventing these protein changes.

KW - Alzheimer's disease

KW - Arp2/3

KW - biomarker

KW - cerebral amyloid angiopathy

KW - complement

KW - cortex

KW - Ephexin-1

KW - glutamatergic synapse

KW - hippocampus

KW - neurodegenerative disease

KW - proteome

KW - Tg-SwDI mouse model

UR - http://www.scopus.com/inward/record.url?scp=105003944046&partnerID=8YFLogxK

U2 - 10.1002/alz.70122

DO - 10.1002/alz.70122

M3 - Journal article

C2 - 40285374

AN - SCOPUS:105003944046

SN - 1552-5260

VL - 21

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 4

M1 - e70122

ER -