Targeting carbonic anhydrases in Alzheimer’s Disease (AD) and Cerebral Amyloid Angiopathy (CAA), effects on neurovascular function, neuroinflammation, clearance, AD pathology

We are studying the effects of carbonic anhydrase inhibitors on vascular health, astrocytic and microglial pro-inflammatory phenotype, Aβ clearance and degradation, in AD/CAA mouse models. We hypothesize that carbonic anhydrase enzymes may represent possible therapeutic targets against Aβ-induced cerebrovascular dysfunction in AD and CAA.

This would be of immediate clinical significance, as many carbonic anhydrase inhibitors are already FDA-approved for other disorders, such as glaucoma and high-altitude sickness.

We are currently using cell and mouse models of amyloidosis and tauopathy to assess the effects of carbonic anhydrase inhibitors and their efficacy to counteract the effects of AD, in the presence or absence of CV risk factors, on mitochondria, neurovascular unit, BBB integrity, neuropathology and cognitive impairment.

Selected Publications:

1- Fossati S, Giannoni P, Solesio ME, Cocklin SL, Cabrera E, Ghiso J, Rostagno A. The carbonic anhydrase inhibitor methazolamide prevents amyloid beta-induced mitochondrial dysfunction and caspase activation protecting neuronal and glial cells in vitro and in the mouse brain. Neurobiol Dis. 2016 Feb;86:29-40. DOI: 10.1016/j.nbd.2015.11.006. Epub 2015 Nov 12. PMID: 26581638; PMCID: PMC4713307.

2- Solesio ME, Peixoto PM, Debure L, Madamba SM, de Leon MJ, Wisniewski T, Pavlov EV, Fossati S. Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity. Aging Cell. 2018 Aug;17(4):e12787. DOI: 10.1111/acel.12787. Epub 2018 Jun 5. PMID: 29873184; PMCID: PMC6052473.

3- Provensi G, Carta F, Nocentini A, Supuran CT, Casamenti F, Passani MB, Fossati S. A New Kid on the Block? Carbonic Anhydrases as Possible New Targets in Alzheimer's Disease. Int J Mol Sci. 2019 Sep 24;20(19):4724. DOI: 10.3390/ijms20194724. PMID: 31554165; PMCID: PMC6801497.

4- Lemon N, Canepa E, Ilies MA, Fossati S. Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer's Disease and Stroke. Front Aging Neurosci. 2021 Nov 16;13:772278. DOI: 10.3389/fnagi.2021.772278. PMID: 34867298; PMCID: PMC8635164.