Led by Dr. Katusic, our lab team is investigating methods to prevent neurodegeneration and studying ways to develop therapeutic strategies that preserve and promote the integrity of the cerebrovascular endothelium. Our work can ultimately help advance treatment for Alzheimer's disease, dementia, cognitive impairment and related disorders in brain function.
We have three main research projects:
- Endothelial dysfunction in cerebral circulation
- Expression and function of amyloid precursor protein in endothelium
- The role of endothelium in microglial function
Endothelial dysfunction in cerebral circulation
Endothelial nitric oxide (NO) is generated by constitutively active endothelial nitric oxide synthase (eNOS), an essential enzyme responsible for cardiovascular function. Historically, endothelial nitric oxide was first recognized as a major vasodilator responsible for control of vasomotor function and local blood flow.
Research studies published by our group support the concept that besides vasomotor function, endothelial NO exerts trophic effects on 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. This research project is designed to define the role of endothelial dysfunction in pathogenesis of neurodegeneration and dementia.
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.
Prior studies from several groups, including our lab team, 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 the 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 are involved 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 endothelium in microglial function
Microglia represent macrophages of the brain and spinal cord. These immunocompetent cells participate in the defense of neuronal tissue against different pathological agents and injury. Microglia cells constantly survey the brain environment. If faced with pathological changes or injured tissue, they may become activated.
Existing evidence suggests that microglia are an important contributor to the pathogenesis of Alzheimer's disease, but their exact role remains unclear.
Our previous studies indicate that genetic inactivation of eNOS has detrimental effects on the function of microglia. These findings indicate that endothelial cells have important influence on microglia function.
We hope to advance scientific knowledge about the mechanistic relationship between brain endothelial cells and microglia, providing a more complete understanding of the vascular contribution to the development of Alzheimer's disease, dementia and cognitive impairment.