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Cerebral proteome adaptations to amyloid angiopathy are prevented by carbonic anhydrase inhibitors
Jasper Carlsen1, Silvia Fossati2, Leif Østergaard3
1Research Unit for Molecular Medicine (MMF), Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.
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.
Insights
Cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD) alters brain proteins. Two FDA-approved carbonic anhydrase inhibitors (CAIs) effectively prevented these detrimental molecular changes in mice.
Area of Science:
- Neuroscience
- Proteomics
- Pharmacology
Background:
- Cerebral amyloid angiopathy (CAA) is a key feature of Alzheimer's disease (AD).
- CAA is associated with adverse effects of emerging AD therapies.
- Understanding CAA's molecular impact is crucial for developing safe and effective treatments.
Purpose of the Study:
- To investigate the molecular effects of CAA in the mouse brain.
- To evaluate the preventative potential of two repurposed FDA-approved drugs against CAA-induced molecular changes.
Main Methods:
- Utilized the Tg-SwDI genetic mouse model exhibiting AD-like deficits and severe CAA.
- Performed brain proteomics on cortical and hippocampal tissues from presymptomatic male and female mice.
Main Results:
- Identified a core set of dysregulated proteins, including AD markers, astrogliosis indicators, and synaptic stability regulators.
- Two repurposed carbonic anhydrase inhibitors (CAIs), acetazolamide and methazolamide, demonstrated efficacy in preventing these molecular adaptations.
Conclusions:
- The study successfully mapped brain proteome alterations in mice with CAA.
- Acetazolamide and methazolamide broadly prevented proteomic adaptations and maintained glutamatergic synapse proteins near wild-type levels.
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