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

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.