Neurovascular circadian oscillation in health and Alzheimer's disease

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ABSTRACT Alzheimer’s disease is a devastating chronic neurodegenerative disease and the leading cause of dementia in older adults. One of the hallmark pathologies of Alzheimer’s disease is the accumulation of extracellular amyloid-beta (Aβ) “plaques” throughout affected regions of the brain. In this grant we aim to understand how two different but potentially inter-related physiological processes, circadian rhythms and the blood-brain barrier (BBB), may interact to regulate the pathophysiology of Alzheimer’s disease. Biological rhythms are orchestrated by the circadian clock and operate in most organisms, and allow for the anticipation of our physiological needs to resonate with the alternating cycles of day and night. They include the daily rhythmicity of the sleep-wake cycle, body temperature, and the metabolic activity of peripheral organs. In recent years, a link between perturbation of circadian rhythms and Alzheimer’s disease was found in studies of both humans and mice. Notably, people with Alzheimer’s disease exhibit profound disruptions to their 24 hour rhythms in sleep-wake and activity patterns, often preceding the onset of clinical symptoms. It has also been found that there is dysfunction of the BBB in Alzheimer’s patients early in the disease, and that biomarkers of this dysfunction may be predictive of future cognitive decline in these individuals. The BBB is a term used to describe the unique properties of the blood vessels that vascularize the central nervous system (CNS). This barrier consists of physical, transport, signaling and metabolic properties that allow the endothelial cells (ECs) that line the blood vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain, thus controlling the extracellular environment of the neural tissue. In our preliminary studies, we have identified that there is a diurnal oscillation to BBB efflux transport, and that this rhythmicity is regulated by the intrinsic expression of the circadian clock regulator BMAL1 within brain ECs. BBB efflux transport has been shown to be critical in the clearance of Aβ from the brain. Therefore, we propose the hypothesis that loss of BBB rhythmicity leads to dysfunction of Aβ clearance, exacerbating the pathophysiology of Alzheimer’s disease. In this proposal we will address several important questions to understand how biological rhythms and the BBB may interact, and how dysfunction of these two physiologies may play a role in the progression of Alzheimer’s disease. First, we will use a series of series of structural, functional, and gene expression analyses across different timepoints of day and night to determine which properties of the BBB display diurnal oscillation. Second, we will determine whether the rhythmicity of the BBB is regulated by the intrinsic EC circadian clock, the central circadian clock in the suprachiasmatic nucleus (SCN), and/or is entrained by light or food. Third, using a mouse model of Alzheimer’s disease, we will determine whether dysfunction of BBB rhythmicity regulates the pathophysiology of Alzheimer’s disease. This proposal will shed light as to whether dysfunction of the EC rhythmicity is an important component of Alzheimer’s disease pathophysiology.