Alzheimer’s disease (AD) often occurs alongside other types of neurological conditions or diseases. Some of the most common are vascular diseases and conditions, often collectively referred to as cerebrovascular disease (CVD). Several mechanisms connect CVD to AD, including weakening of the blood-brain barrier, impaired clearance of toxic products from the brain, and disruptions of cerebrospinal fluid dynamics. Dr. Lo has long studied how circadian disruptions influence the brain’s blood vessels and contribute to both CVD and AD. In previous studies, Dr. Lo has shown that the cells that make up blood vessels experience significant circadian rhythms, leading him to hypothesize that they would also be subject to disruptions caused by impaired circadian rhythms, such as those observed in AD. This represents a potentially vicious cycle where the disruption of the blood vessels worsens AD pathologies, which worsens circadian rhythm disruptions, which further disrupts the blood vessels, and so on. Here, Drs. Lo and Harrington believe that correcting the circadian clocks of the cells in the blood vessels can stop this cycle and slow or prevent AD progression and cognitive decline.
The team proposes three aims for this project. In the first, they will define the cumulative impact of CVD and AD pathologies on the clock gene patterns of cells in the brain’s blood vessels. This aim will validate Dr. Lo’s previous work in each model independently and provide a baseline against which treatments in later aims can be compared. The second aim will focus on the cumulative effects of amyloid and a major feature of CVD: hypoxia (oxygen insufficiency). While most people are familiar with hypoxia at the whole-body level, individual cells and systems in the body can also become hypoxic. In CVD, blood flow to the brain can be impaired, reducing the amount of oxygen reaching brain cells. Drs. Lo and Harrington hypothesize that hypoxia and amyloid pathology can cause severe disruption to blood vessel cells, and that these disruptions extend to the clock genes and their rhythms. In cell culture, the team can expose cells to hypoxic conditions and/or amyloid pathology to determine the independent and cumulative effects on clock genes. For the final aim, they will test the same novel circadian-strengthening therapy used by Dr. Musiek’s team to restore circadian rhythms in blood vessels and thereby limit AD pathology progression and cognitive decline. Drs. Lo and Harrington will compare these results with those from Aim 1, as they will utilize the same mice with both amyloid pathology and CVD pathology.
Overall, this project aims to define how CVD and AD influence circadian rhythms at the level of the brain’s blood vessels and to test a novel therapeutic to prevent the vicious cycle of pathologies and disruptions that could slow or prevent AD progression.
