The overarching goal of the Pires laboratory is to investigate how normative aging and neurodegenerative diseases, such as Alzheimer’s disease, affect the function of cerebral blood vessels, contributing to progression of cognitive decline and, over time, dementia. In order to complete the studies in our lab, we use a multi-scale approach: from molecule to behavior. Under this umbrella, we have different projects focused on specific aspects of cerebral vascular regulation (details below).
Post-translational modification of vascular ion channels in Alzheimer’s disease and related dementias. Real-time regulation of blood flow to the brain is dependent on the ability of the blood vessels to change their diameter (termed vasoreactivity) in response to the metabolism of brain cells. Vasoreactivity, in turn, requires opening of ion channels in endothelial and vascular smooth muscle cells. Activity of ion channels can be modified at many different levels, including by post-translational modification, which are addition or removal of different chemical radicals to specific aminoacids in the ion channel structure (for example, phosphorylation, oxidation, nitrosylation, etc.). In the Pires lab, we are are currently investigating how oxidation and nitrosylation affect the function of specific vascular ion channels, and if these processes are increased in Alzheimer’s disease or related dementias.
Calcium dynamics and cerebral microvascular regulation. Another research interest in the lab is how intracellular calcium homeostasis is affected by the aging process and in the context of neurodegenerative diseases. Calcium is a versatile and ubiquitous signaling molecule, and changes in intracellular calcium are central to both dilation and constriction of the cerebral microvasculature. Consequently, alterations in vascular calcium homeostasis, caused by pathological molecules associated with neurodegeneration, can have a profound impact on blood flow regulation in the brain, which may underlie progressive cognitive decline. We use a combination of molecular / biochemical, cellular (electrophysiology) and high-resolution tissue imaging (video on the left) to study calcium signaling in both endothelial and vascular smooth muscle cells.
Neurovascular function in models of late-onset Alzheimer’s disease (LOAD). Apolipoprotein E (ApoE) is a circulating protein important for transport of cholesterol across the body. ApoE is found in 3 isoforms in the human population: ApoE2, ApoE3 and ApoE4. Of those, ApoE4 is associated with an increased risk of developing sporadic Alzheimer’s disease in the population. In our lab, we are currently using models of human ApoE4 knock-in to evaluate age-dependent cerebral microvascular and neurovascular function, as well as possible cognitive decline.
Lymphatic function in Alzheimer’s disease. Lymphatic vessels are part of a specialized circulation responsible for draining fluid from tissues, removal of toxic metabolites and accumulated proteins, and immune surveillance throughout the body. In recent years, lymphatic drainage of the brain, termed glymphatic drainage, has taken center stage as a possible mechanism involved in progression of neurodegenerative and neurological disorders, including Alzheimer’s disease, Parkinson’s diseases, stroke and traumatic brain injury. In the Pires laboratory, we are investigating how misfolded proteins associated with neurodegeneration affect the function of lymphatic vessels, and possible mechanisms involved in such alterations.
These are only a few examples of ongoing research projects in our laboratory. Interesting in knowing more? E-mail Dr. Pires at ppires@arizona.edu to schedule a visit and learn about how you can get involved in our studies!