CHOPped—NIH grants $1.4 million to study cutting dietary link to Alzheimer’s

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School of Medicine & Health Sciences


GRAND FORKS, N.D. — The National Institutes of Health has granted $1.4 million to Associate Professor Othman Ghribi, Ph.D., in the Department of Basic Sciences at the University of North Dakota School of Medicine and Health Sciences, to pursue research on a possible dietary link to Alzheimer’s disease (AD). The five-year R01 grant from the NIH’s National Institute on Aging funds research that focuses on a specific dietary agent and its role in the expression of genes that are disease related. R01 grants are the highest level of research supported by the NIH.

“The cause of AD is not well defined,” Ghribi said. “But it is likely that the interplay between environmental (chemical and dietary) factors and genetic susceptibilities plays a key role in the origin and development of this disease.”

“A serious impediment to the development of disease-modifying treatments for AD is the limited knowledge of the pathogenesis of the disorder. AD is likely a multifactorial disease, with several factors contributing to its pathogenesis,” Ghribi said. “The role played by genetics in the etiology of AD has long been recognized with the evidence that mutations in specific genes underlie the familial-inherited forms of AD. However, the causes of the sporadic forms, that represent the vast majority of AD cases, are not well-known.”

Ghribi’s work examines the link between a specific dietary agent — palmitate — and a specific transcription factor that may affect the development of AD. Transcription factors are proteins — the building blocks that make all organisms function — that control which genes are turned on or off in the genome. The transcription factor known to scientists as CHOP or GADD153 may work in concert with palmitate to cause AD-like pathology.

Palmitate is a fatty acid found in various common foods that people consume every day, including meat, milk, butter, and cheese. The body can also produce palmitate if a person’s diet is rich in carbohydrates. High levels of palmitate have been shown to reduce the body’s ability to burn fat, lower energy levels, inhibit the uptake of glucose, and may potentially increase the risk of obesity and insulin resistance, both of which are risk factors for AD.

“While the role of diet in modulating AD is still uncertain in general, following specific diets such as the Mediterranean diet that has fewer saturated fats are suggested to reduce the risk for AD,” Ghribi said. “And dietary supplements containing key nutrients were recently shown to improve cognition in patients with dementia. Conversely, diets rich in saturated fats like palmitate may increase the risk for AD.”

In addition, when combined with trans fats — what many doctors consider to be the worst fats you can eat, according to the Mayo Clinic — palmitate increases low-density lipoprotein (LDL) or “bad” cholesterol and reduces high-density lipoprotein (HDL) or “good” cholesterol, subsequently promoting atherosclerosis and cardiovascular disease, both of which are also suggested to increase the risk for AD.

Accumulation in the brain of the molecule amyloid-β (Aβ) is a major component in the mechanisms behind Alzheimer's disease.

“A recent cross-sectional analysis showed indeed that elevated cerebral Aβ levels in humans with AD is associated with high LDL and low HDL levels,” Ghribi said.

Data from Ghribi’s research have shown increased CHOP levels in brains from mouse models of AD, and that silencing CHOP precludes palmitate-induced increases in Aβ levels. In line with his findings are data showing that CHOP can regulate the expression of genes and proteins related to AD. Inside cells is an organelle called the endoplasmic reticulum (ER) that is fundamental to proper cell functioning. It is the site where proteins are synthesized, folded and assembled before being transported to run the cell. Intense or sustained stress to the ER can be triggered by chemical, dietary, genetic, or pathological factors that activate CHOP, which then arrests cell growth and damages DNA.

“Using existing or designing new drugs that inhibit CHOP might be promising targets for determining their translational potential as treatments to reduce the progression of AD,” Ghribi said. “Based upon the information we will learn from this proposal, future experiments can be designed to screen for agents that can specifically regulate CHOP. Identification of drugs that can reduce CHOP expression and protect in animal models for AD may prove to be potential candidates that can translate to screening for AD therapies in humans. Also of potential significance is that increased plasma levels of palmitate or of indicators of ER stress such as CHOP may also provide diagnostic tools and biomarkers for AD.”

A part of the U.S. Department of Health and Human Services, the NIH is the nation’s medical research agency. The NIH is the largest source of funding for medical research in the world. The mission of the NIH is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.