Research

Dr. Katusic's team is investigating methods to prevent neurodegeneration and studying ways to develop therapeutic strategies that preserve and promote integrity of the cerebrovascular endothelium. Dr. Katusic's hope is that this research will help improve treatment options for stroke, cognitive impairment and Alzheimer's disease.

Dr. Katusic's research has been funded by the National Institutes of Health, the American Heart Association, and many other funding agencies and organizations.

Our lab has three main research projects.

Endothelial dysfunction in cerebral circulation

Endothelial nitric oxide (NO) is generated by constitutively active endothelial NO synthase (eNOS), which is an essential enzyme responsible for cardiovascular function. Endothelial nitric oxide has been recognized as a major vasodilator responsible for control of vasomotor function and local blood flow.

Our team's published research studies support the concept that besides affecting vasomotor function, endothelial NO affects function of neuronal cells and microglia.

Indeed, loss of endothelial NO increases expression and function of amyloid precursor protein (APP) and the protease β-site APP-cleaving enzyme 1 (BACE1). This, in turn, increases production of amyloid-β (Aβ) peptide, which is considered a pivotal perpetrator of the neurovascular pathology that defines Alzheimer's disease. Moreover, eNOS deficiency promotes tau phosphorylation in neuronal tissue, thus providing another critical link between endothelial dysfunction and the pathogenesis of Alzheimer's disease.

The exact signaling pathways responsible for the observed effects of endothelial nitric oxide remain to be defined. Our research project is designed to determine the role of endothelial dysfunction in the pathogenesis of neurodegeneration and cognitive impairment.

Expression and function of amyloid precursor protein in endothelium

Amyloid precursor protein belongs to the family of transmembrane glycoproteins highly expressed in the human brain. APP is the only member of the family encoding Aβ peptides, which are considered major culprits in the pathogenesis of Alzheimer's disease.

Previous studies from our team and several other research groups established high expression of APP in endothelium of cerebral and systemic arteries. Still, the vascular function of amyloid precursor protein is poorly understood.

Notably, expression of amyloid precursor protein is significantly higher in the cerebral arteries than in the systemic arteries. Under physiological conditions, endothelial APP is predominantly cleaved by α-secretase, thereby resulting in production and secretion of soluble amyloid precursor protein α (sAPPα) into the lumen of blood vessel walls.

Interestingly, prostacyclin (PGI₂) exerts a stimulatory effect on expression and α-processing of APP. Thus, both nitric oxide and PGI₂ participate in the regulation of endothelial APP function. Indeed, NO suppresses β-processing, whereas PGI₂ promotes α-processing of APP.

Our efforts in this research project are directed at advancing the hypothesis that sAPPα has an important vascular protective function. Our goal is to define the nature of vascular protection mediated by production of sAPPα and to determine endothelial receptors and signal transduction pathways activated by sAPPα.

The role of endothelial dysfunction in the pathogenesis of cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) caused by cerebrovascular deposition of amyloid-β is common in older people and it is an important instigator of intracerebral hemorrhage and age-related cognitive decline.

CAA is clinically distinct from Alzheimer's disease. However, people with Alzheimer's disease typically have significantly more severe cognitive impairment when they also have CAA. There's no disease-specific treatment available for people with cerebral amyloid angiopathy.

Current understanding of CAA pathogenesis is based on evidence that impaired clearance of Aβ from the brain interstitial fluid drives deposition of Aβ in blood vessel walls. Our hypothesis is that dysfunctional endothelium promotes cerebrovascular deposition of Aβ. In previous studies with experimental models of CAA, we established that increased production of Aβ in cerebral blood vessels precedes increased production of Aβ in the brain parenchyma, thereby causing initial deposition, called seeding, of Aβ.

We're studying the mechanisms underlying the relationship between endothelial dysfunction and increased production and deposition of Aβ in cerebral blood vessels. We anticipate that improved understanding of vascular mechanisms responsible for development of CAA pathology will enable development of new therapeutic approaches.