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Can damage to thread-like extensions on cells near blood vessels contribute to the underlying biology of Alzheimer’s?
Wissam AbouAlaiwi, Ph.D.
University of Toledo Health Science Campus
Toledo, OH - United States
Background
According to many studies, hypertension (high blood pressure) may promote one’s risk for Alzheimer’s. While the exact mechanisms linking Alzheimer’s risk and hypertension remain unclear, current research suggests endothelial cells may be involved. Endothelial cells line blood vessels to help transport blood, nutrients and oxygen into the brain and transport harmful proteins (such as dementia-related beta-amyloid and tau) out of the brain.
Endothelial cells have specialized threadlike projections called cilia, which help maintain the cells’ functions. In some individuals, cilia can become damaged or structurally impaired contributing to a type of disorder (called a ciliopathy) known to contribute to hypertension. Research has found that individuals with ciliopathies produce less nitric oxide, a compound important in maintaining blood vessel function. Ciliopathies may also impair the function of molecules called muscarinic M3 receptors (AchM3Rs), which help instigate the release of nitric oxide. Low nitric oxide levels have been shown to contribute to both cerebrovascular (brain blood vessel) disease and high brain levels of beta-amyloid, a key hallmark of Alzheimer’s.
Research Plan
Dr. Wissam AbouAlaiwi and colleagues will examine endothelial cells from individuals who had ciliopathies and Alzheimer’s-like mice engineered to lack AchM3Rs. First, the researchers will study how abnormal cilia structure – as well as reduced AChM3R activity – may contribute to lower levels of nitric oxide in the human cells. They will also treat the cells with human beta-amyloid and determine whether the amyloid promotes further damage to the cilia. Second, the investigators will examine whether the loss of AchM3R in their genetically-engineered mice contributes to reduced nitric oxide levels, high blood pressure and cognitive (brain function) impairment in the animals.
Impact
Results from this study will shed new light on the molecular links between hypertension and Alzheimer’s. They could also identify cilia disorders as primary targets for both dementia and heart disease therapies.
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