Research Spotlight

Graham & Howell Spotlight

Neuroinflammatory Responses to Western Diet (right) Compared to Control Chow (left)

Western Diets Linked to Neuroinflammation

A growing number of studies identify obesity and dietary factors as having deleterious effects on the brain that cause or contribute to cognitive deficits with age. Environmental risk factors such as diet and levels of physical activity are also critical factors in neurodegenerative disease such as Alzheimer’s disease (AD). Currently, more than 35% of Americans over the age of 65 are obese, and this number is on the rise, with the obesity epidemic hitting an all time high. Some studies suggest obesity, particularly mid-life obesity, increases the chances of cognitive decline and AD by six-fold. One environmental factor that has been consistently implicated for increased risk of obesity and AD is the high sugar, high fat, animal-based diet prevalent in the United States and other industrialized countries. The so-called “western” diet, combined with a sedentary lifestyle, has been shown to contribute to a high percentage of AD cases, perhaps as much as 25%. But while the association is strong, the actual causal mechanisms are still poorly understood.

Research in the lab of Dr Gareth Howell at The Jackson Laboratory dissects the genetics and genomics of neurodegeneration, with a particular interest in AD. He and his lab are working to develop improved mouse models for late onset AD and to employ them to investigate the molecular mechanisms underlying neuronal loss and disease pathology. Understanding and identifying the early factors that lead to clinical disease provides an opportunity to develop effective treatments and possible preventative therapeutics. The lab is assessing the effects of environmental risk factors like diet and inactivity and how they combine with the underlying genetics to increase or decrease disease risk for AD.

To learn more about the connection between diet and AD-related neurodegeneration, Howell and Mammalian Genetics PhD student Leah Graham utilized a westernized mouse diet developed by their collaborator Dr Simon John. We hypothesized that a western diet would worsen the neurodegeneration seen in the APPswe/PSEN1de9 mouse model of AD. Leah fed this mouse model of AD the western diet and compared them to mice fed the normal vegetable-based chow. The results were dramatic. In a paper published in Nature Scientific Reports, Howell and Graham show an increase in astrocytosis and microglial and monocyte activity in the brains of mice that consistently ate the western diet chow, indicating a severe neuroinflammatory response. The finding is potentially significant because of previous findings that have linked components of western diet to increased peripheral inflammation over time. Furthermore, β-amyloid plaque deposition increased in the brains of the western diet mice.

As a part of her thesis, Leah developed a technique of sorting populations of immune cells out aging brains from western diet-fed mice. Further studies done by Leah in the lab are currently characterizing the innate immune response to the western diet in both the brain and the peripheral immune system to determine the effects on the brain during aging. We have now sequenced these subpopulations of cells and Leah will be identifying differences in gene expression between the groups of cells that are resident or have infiltrated into the brain. In addition, she is looking at the effects diet-induced neuroinflammation caused on cognition and myelin turnover in C57BL/6J mice. Finally, Leah is determining the effects of exercise by voluntary running on the aging brain in diet-induced obese mice.

Graham LC, Harder JM, Soto I, de Vries WN, John SW, Howell GR. 2016. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer's disease. Sci Rep. 6: 21568. books

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