New research from the US suggests that a blood vessel dysfunction already linked to cardiovascular disease may also account for the build up of amyloid plaques in the brain, a characteristic trait of Alzheimer’s disease.
The study was the work of senior author Dr Zvonimir S. Katusic, and colleagues Dr Susan Austin and Anantha V. Santhanam, all from the Mayo Clinic in Rochester, Minnesota. A write up of their study was published online on 2 December in Circulation Research, a journal of the American Heart Association (AHA).
According to estimates from the National Institutes of Health, as many as 5 million Americans are living with Alzheimer’s disease, a progressive brain condition that typically affects people age 60 and older, gradually depriving them of memory, reasoning and other cognitive skills to the point where they can no longer hold a conversation or take care of themselves.
Previous studies have already suggested people with several cardiovascular risk factors are also at higher risk of developing Alzheimer’s disease, but the nature of these links was somewhat unclear.
However, one common biological feature of these cardiovascular risk factors is lack of nitric oxide in the endothelium, the layer of cells that lines the walls of blood vessels.
Katusic, who is a a professor of anesthesiology and pharmacology at the Mayo Clinic, told the press that:
“If you look at any risk factor for cardiovascular disease — the standard risk factors like high cholesterol, diabetes, hypertension, smoking, sedentary lifestyle, aging — all of these have been associated with loss of nitric oxide in the endothelium, a condition known as endothelial dysfunction.”
Nitric oxide (NO) plays an important role keeping blood vessels open (vasodilation) so blood can flow unimpeded and deliver oxygen and nutritients to surrounding tissue, including the brain.
Alzheimer’s disease has two distinct hallmarks, found in the brains of people who have died of the disease: one is found inside brain cells or neurons and the other in the space between neurons. The one that occurs inside brain cells is called “neurofibrillary tangles”, comprising twisted tangles of fiber made of of tau protein. The one that occurs between brain cells is a build up of fragments made of amyloid beta peptides (the so-called “amyloid plaques”).
The researchers were particularly interested in the second characteristic: the amyloid plaques, and the role that nitric oxide (NO) in the endothelium might play in the expression and processing of a protein called amyloid precursor protein or APP, the raw material for making amyloid beta peptides.
Using endothelial cells from microscopic blood vessels in the human brain, Katusic and colleagues chemically inhibited eNOS (endothelial nitric oxide synthase), an enzyme involved in nitric oxide production.
This triggered a series of biochemical reactions that led to increased production of APP plus higher levels and activity of BACE1, an enzyme that cleaves APP to produce the amyloid beta peptides that make up the plaques.
Austin, first author and a postdoctoral fellow at the Mayo Clinic, said:
“Once you lose that basal nitric oxide, you see the increases in APP and BACE1, and the increase in amyloid beta generation.”
The researchers also looked at microscopic blood vessels in the brains of mice that had been genetically modified to lack the eNOS enzyme. Such mice naturally have higher blood pressure and are prone to insulin resistance, compared to normal mice.
They found that the microscopic blood vessels in the brains of the modified mice had half the normal amount of nitrates and nitrites, chemicals that indirectly indicate levels of nitric oxide production.
And the eNOS-deficient mice also showed higher levels of APP, BACE1 and amyloid beta in the brain.
The researchers concluded that:
“Our data suggest that endothelial NO plays an important role in modulating APP expression and processing within the brain and cerebrovasculature.”
They suggested that the associated pathway may serve as an important therapeutic target in preventing and treating mild cognitive impairment as well as Alzheimer’s disease.
Katusic said the study also suggests that “preserving a healthy blood vessel wall is important in preventing cognitive impairment and ultimately Alzheimer’s disease”.
“On the cardiovascular side we’ve known for some time that preservation of healthy endothelium is critical to prevent major cardiovascular events. Now it seems this may have important implications for cognitive impairment,” he added.
The study may also explain why exercise is good for the cardiovascular health and the aging brain, said Katusic.
“There is a lot of literature showing that every time you exercise, you stimulate the endothelium to produce more nitric oxide,” he explained.
Funds from the National Institutes of Health, the Mayo Alzheimer’s Disease Research Center, an American Heart Association Scientist Development Grant, Clinical Pharmacology Training Grant and The Mayo Foundation helped pay for the research.
“Endothelial Nitric Oxide Modulates Expression and Processing of Amyloid Precursor Protein.”
Susan A. Austin, Anantha V. Santhanam,and Zvonimir S. Katusic.
DOI:10.1161/CIRCRESAHA.110.233080
Additional source: AHA.
Written by: Catharine Paddock, PhD