Supplement: Calpains and Abdominal Aortic Aneurysms

The etiology of cognitive dysfunction is closely linked to various cardiovascular risk factors. Angiotensin II (AngII), a bio-active peptide of the renin-angiotensin system contributes to cardiovascular diseases. Recent compelling evidence provides a link between AngII and cognitive dysfunction and neuropathology. The parent grant examines the role of calpain-2 during AngII-induced abdominal aortic aneurysm development. Calpain-2 is a potential target for Alzheimer’s disease as: 1) Calpain-2, a calcium dependent cysteine protease, is highly expressed in brains of Alzheimer’s patients and 2) Pharmacological inhibition of calpain-2 improves memory function in preclinical rodent studies. Additionally, mice infused with AngII have impaired memory function and altered expression of various genes involved in Alzheimer’s disease development. However, the potential mechanisms by which AngII mediates its effect on Alzheimer’s disease is undetermined. This Administrative Supplement will test a novel hypothesis that AngII promotes cognitive dysfunction and cerebral vascular pathologies by augmenting calpain-2 activation in the brain. We will use our well- established AngII-infusion mouse model as well as a unique inducible whole body calpain-2 deficient mouse model described in the parent grant. Mice (both male and female) will be infused with AngII to answer the following questions that are within the scope of the parent grant: A: Will AngII infusion augment cognitive decline and cerebral pathology via calpain-2 activation? B. Is this AngII-calpain-2 driven process of cognition dysfunction and brain pathology independent of blood 19 pressure? C. Determine the association and correlation between brain calpain-2 and plasma AngII to cerebral vascular pathologies in Alzheimer’s patient samples? The proposed project will be benefitted from (1) Water maze to determine cognitive function in our Rodent Behavior Core, (2) sophisticated Light Microscopy Core on campus that permits detailed characterization of cerebral vascular structure in mice, and (3) our well-respected Alzheimer's Disease Center Core Tissue Bio Bank and collaboration with neurological scientists (Dr. Johnson and Dr. Nelson at our institutional Alzheimer's Disease Center). We are confident that results from this Administrative Supplement will produce preliminary data to develop an R01 that focuses on providing new insights into understanding mechanisms of Alzheimer’s disease. The potential R01 application will be strengthened by novel mouse models, and pharmacological and molecular tools that have been developed in the parent grant, well-recognized AD mouse models in our Alzheimer's Disease Center and this transdisciplinary team of scientists.