Health for life

Researchers at the Linda Crnic Institute for Down Syndrome and the University of Colorado School of Medicine have found that a single mechanism may underlie the damaging effect of cholesterol on the brain and on blood vessels.

High levels of blood cholesterol increase the risk of both Alzheimers disease and heart disease, but it has been unclear exactly how cholesterol damages the brain to promote Alzheimers disease and blood vessels to promote atherosclerosis.

Using insights gained from studying two much rarer disorders, Down Syndrome and Niemann Pick-C disease, researchers at the Linda Crnic Institute for Down Syndrome and the Department of Neurology of the University of Colorado School of Medicine found that cholesterol wreaks havoc on the orderly process of cell division, leading to defective daughter cells throughout the body.

In the new study published this week in the on-line journal PLOS ONE, Antoneta Granic, PhD, and Huntington Potter, PhD, show that cholesterol, particularly in the LDL form, called bad cholesterol, causes cells in both humans and mice to divide incorrectly and distribute their already-duplicated chromosomes unequally to the next generation. The result is an accumulation of defective daughter cells with the wrong number of chromosomes and theore the wrong number of genes. Instead of the correct two copies of each chromosome, and thus two copies of each gene, some cells acquired three copies and some only one.

Granic and Potters study of the effects of cholesterol on cell division included a prominent finding of cells carrying three copies of the chromosome (#21 in humans and #16 in mice) that encodes the amyloid peptide that is the key component of the neurotoxic amyloid filaments that accumulate in the brains of Alzheimer patients.

Human trisomy 21 cells are significant because people with Down syndrome have trisomy 21 in all of their cells from the moment of conception, and they all develop the brain pathology and many develop the dementia of Alzheimers disease by age 50. Earlier studies by Granic, Potter and others have shown that as many as 10% of cells in an Alzheimer patient, including neurons in the brain, have three copies of chromosome 21 instead of the usual two. Thus, Alzheimers disease is, in some ways, a form of acquired Down syndrome. Furthermore, mutant genes that cause inherited Alzheimers disease cause the same defect in chromosome segregation as does cholesterol, thus indicating the presence of a common cell division problem in both familial and sporadic (non-familial) Alzheimers disease.

The new research also found trisomy 21 neurons in the brains of children with what, until now, was thought to be an unrelated neurodegenerative disease (Niemann Pick type C), caused by a mutation affecting cholesterol physiology. This result suggests that neurodegeneration itself might be linked to chromosome missegregation.

Such a model is supported by the finding of Thomas Arendt, MD, and colleagues at the University of Leipzig that 90% of the neuronal cell death observed at autopsy in Alzheimer patients is due to the creation and selective loss of neurons with the wrong number of chromosomes.

Identifying the specific problem caused by cholesterol will lead to completely new approaches to therapy for many human diseases, including Alzheimers disease, atherosclerosis and possibly cancer, all of which show signs of defective cell division. Granic and Potter already have found a potentially simple approach to preventing cholesterol from causing cells to distribute their chromosomes unequally into their new daughter cells. Specifically, when cells in culture were first treated with ethanol, the subsequent exposure to bad cholesterol was without effect on cell division: Each daughter cell received the correct number of chromosomes.

Researchers publishing in the journal Nutrition show that Omega-3 fatty acids found in fish and natural foods including nuts and seeds can lower levels of dangerous homocysteine, an amino acid linked with increased risk of cardiovascular disease and dementia. Reviewing data from eleven trials including more than 720 study participants, scientists found that introducing Omega-3 fats from dietary or supplemental sources were associated with significantly lowered levels of plasma homocysteine.

Consumption of whole walnuts or their extracted oil can reduce cardiovascular risk through a mechanism other than simply lowering cholesterol, according to a team of Penn State, Tufts University and University of Pennsylvania researchers.

"We already know that eating walnuts in a heart-healthy diet can lower blood cholesterol levels," said Penny Kris-Etherton, Distinguished Professor of Nutrition, Penn State. "But, until now, we did not know what component of the walnut was providing this benefit. Now we understand additional ways in which whole walnuts and their oil components can improve heart health."

In a randomized-controlled trial, the researchers gave 15 participants with elevated blood cholesterol one of four treatments -- either 85 grams of whole walnuts, 6 grams of skin, 34 grams of defatted nutmeat, or 51 grams of oil. The team evaluated biochemical and physiological responses in the participants before the treatments were administered and again 30 minutes, one hour, two hours, four hours and six hours after administering the treatments. The researchers repeated this process for each of the remaining three treatments.

Results -- which will appear in the June 1 issue of the Journal of Nutrition and are now online -- showed that a one-time consumption of the oil component in walnuts favorably affected vascular health. In addition, consumption of whole walnuts helped HDL -- good cholesterol -- perform more effectively in transporting and removing excess cholesterol from the body.

"Our study showed that the oil found in walnuts can maintain blood vessel function after a meal, which is very important given that blood vessel integrity is often compromised in individuals with cardiovascular disease," said Claire Berryman, graduate student in nutritional sciences, Penn State. "The walnut oil was particularly good at preserving the function of endothelial cells, which play an important role in cardiovascular health."

According to the researchers, walnuts contain alpha-linolenic acid, gamma-tocopherol and phytosterols, which may explain the positive effects of the walnut oil treatment.

"Implications of this finding could mean improved dietary strategies to fight heart disease," said Berryman. "The science around HDL functionality is very new, so to see improvements in this outcome with the consumption of whole walnuts is promising and worth investigating further."

Further studies are needed to determine the mechanisms that account for cardiovascular disease risk reduction with walnut consumption, according to Kris-Etherton.

"Our study indicates that simple dietary changes, such as incorporating walnuts and/or their oil in a heart healthy diet, may reduce the risk of heart disease," she said.