Current Projects

Cerebrovascular dysfunction in Alzheimer’s disease

Throughout the human body there are specialized, dynamic and complex cellular barrier interfaces that play a central role in tissue and neuronal homeostasis. The cerebrovasculature is the largest interface of blood-to-brain contact, and every neuron is supplied by its own capillary. Dynamic processes at the cerebrovasculature prevent the uptake of unwanted molecules from the blood, remove waste products from the brain and supply essential nutrients and signaling molecules to the brain. In Alzheimer’s disease (AD) there is evidence that all these critical functions of the cerebrovasculature are disrupted. However, the extent that cerebrovascular dysfunction contributes to neuronal dysfunction in AD is unclear. Addressing these issues is important for understanding whether cerebrovascular dysfunction is a potential therapeutic target for AD. Our goal is to identify how risk factors for AD modulate the different types of cerebrovascular dysfunction, and whether this contributes neuronal dysfunction using in vitro and in vivo approaches. Further, we are focused on identifying mechanistic pathways in specialized brain endothelial cells that could underlie cerebrovascular dysfunction and serve as therapeutic targets.

Stress, sex and APOE in Alzheimer’s disease

The function of multiple neuronal sub-types is altered in aging and Alzheimers disease (AD). In addition, there is evidence that AD risk factors may differentially modulate neuronal subtype function. Our research has identified that the combination of stress, female sex, and APOE4 results in a distinctive phenotype of neuron function. In addition, we have uncovered a potential link among these AD-risk factors, altered neuronal function and epidermal growth factor. Our ongoing studies aim to understand in detail how stress, sex and APOE interact to alter neuron function.

Angiotensin signaling in Alzheimer's disease

The angiotensin system has been classically studied for its role in controlling blood pressure in the periphery. However, increasing evidence suggests that a local brain angiotensin system is important for cognition. Indeed, the angiotensin system is linked to brain regions, cell types, and functions that are involved in learning and memory. These lines of evidence have led to the idea that disruption in angiotensin receptor signaling contributes to neuronal dysfunction in AD; however, direct evidence is lacking. In this project our goal is to evaluate whether an imbalance in the brain angiotensin system contributes to neuronal dysfunction in models of AD-like pathology, using a combination of preclinical therapeutic and mechanistic in vivo and in vitro research.

DHA treatment for Alzheimer’s disease

DHA (docosahexaenoic acid, 22:6, n-3) is an essential fatty acid that is important for learning and memory and acts through similar pathways that are disrupted by APOE4 in Alzheimer’s disease (AD). DHA deficiency is associated with cognitive decline in aging, which may be particularly pronounced with APOE4. Indeed, current research suggests that APOE4 lowers the amount of DHA delivered to cells in the brain. However, observation studies and clinical trials with DHA supplements have produced mixed and largely disappointing results in aging and AD. An important contributing factor is that the currently available molecular forms of DHA may not enrich brain DHA levels sufficiently to improve neuronal function. Thus, optimizing molecular forms of DHA to enrich brain DHA may be particularly beneficial for APOE4 carriers at reducing age-related cognitive decline. In a collaborative project we are evaluating the activity of a novel molecular form of DHA in preventing age-related memory deficits, enriching brain DHA and modulating pathways in the brain that are important for neuronal function in mice.