Understanding Alzheimer's
Early diagnosis is important, but diet and exercise may be as critical.
Alzheimer's disease is the most common form of dementia, a progressive, age-related neurodegenerative disorder that can rob its victims of even the most basic functions of memory and meaning. As our population grows older, the incidence of Alzheimer’s is rising dramatically.
At The Jackson Laboratory (JAX), neurobiologist Gareth Howell, Ph.D., is working toward solutions.
“Alzheimer’s disease is the HIV-AIDS of our age,” he says. “It’s front and center in so many people’s lives, directly or indirectly. So far, our mouse models have enabled understanding aspects of the biology of the disease. But we need better models now to identify and test the drugs that will work best against Alzheimer’s disease.”
Recent studies have revived interest in therapeutics that have proven disappointingly ineffective in slowing or reversing the course of Alzheimer’s. Now, some of these same drugs have been shown to work better if the disease is caught and treated early on. So the Howell lab is using genetic and genomic approaches to identify changes that flag the earliest stages of the disease, before the characteristic amyloid plaques begin forming on the brain’s neural cells and before sticky tangles of broken protein strands begin congesting the neurons.
In addition, and working in partnership with colleagues at Cardiff University, Howell’s lab is using new analytic tools to untangle the genetic configurations that set the stage for Alzheimer’s. But Howell says it is clear that for many individuals, lifestyle plays an essential role in determining the risk of developing the disease.
“For some, it’s the intersection of genetics, lifestyle and aging that ultimately determines whether or not you get Alzheimer’s disease,” says Howell. So his team works with mouse models to measure the impact of diet and exercise, in combination with aging processes, on the risk of developing Alzheimer’s.
“I felt we could make a real difference”
Howell, a native of Wales, completed his undergraduate studies in molecular biology at The University of Manchester, UK, in 1993. Throughout his graduate studies, he worked at the Sanger Institute’s Wellcome Trust Genome Campus, in Cambridge, UK, where he was part of the research team that helped sequence the first complete human genome.
“Once we did that, we had the parts list, but we still didn’t really understand how the genome worked,” he recalls. “I saw then that what I really wanted to do with my career was to understand how genes in humans work by understanding how they function in a model organism, the mouse. And there’s only one place on the planet where you would want to go to learn mouse genetics, and that’s The Jackson Laboratory.”
He did a postdoctoral fellowship at JAX in 2003, then returned in 2005 as a Research Scientist. He was promoted to Assistant Professor in 2012.
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At JAX, Howell became interested in the mechanisms that underlie the processes of aging and its attendant disorders. “When I first came back to JAX [in 2005], I worked in the lab of Howard Hughes Investigator Simon John, who was applying genetic and genomic approaches to understanding glaucoma. We did a lot of work in identifying the early stages of glaucoma in mice,” he says.
“And as I began to think about transitioning to my own lab, I realized that similar approaches could be applied to studying Alzheimer’s disease. I felt that we could make a real difference in using the unique resources we have at JAX to learn more about Alzheimer’s disease.”
It’s a timely focus. Not only is the American population aging with the Baby Boom of the 1940s and 1950s, but many in that group are also affected by obesity related to poor diet and inadequate exercise. And aging and obesity are both associated with loss of cognitive function, Alzheimer’s diseaseAD and other forms of dementia.
“So those people may have an increased risk of Alzheimer’s disease,” Howell says of the Boomer generation. “My major motivation is to prevent or slow its progress of Alzheimer’s disease. It’s a disease of the elderly, so if you can prevent it or delay the onset by a decade or two, that’s a huge improvement in quality of life.”
Lifestyle factors alter immune responses in the brain
The typical mouse, both in the wild and in the lab, eats a “pretty healthy vegan” diet, Howell says—plant-based, high in vitamin and mineral content, low in fats and proteins. Howell’s lab worked with Simon John, who had developed a diet for mice that models the diet consumed in the western world. They have determined that mice fed their regular diet demonstrate healthy brain function for longer as they age compared to mice fed the western diet.
Mice maintained on the western diet—which contains animal proteins, increased fats and decreased micronutrients—often develop a chronic state of inflammation in their brains and the rest of their bodies. This inflammation is an element of the immune response, an otherwise healthy reaction to allergens, infections and trauma. But on a sustained basis, inflammation causes problems of its own.
“Our hypothesis is that these immune responses we’ve been seeing in the brain, and systemically, play a major role in ultimately leading to brain dysfunction, including cognitive decline and an increased risk for Alzheimer’s disease,” Howell says.
In related studies, mice who are allowed to exercise normally by running on a spinning wheel maintain a healthy cognitive function longer than those who are allowed only limited activity, Howell notes, and their brains are slow to develop the amyloid plaques associated with Alzheimer’s disease,AD compared with their more sedentary peers.
All of these changes in the mouse brain tissue can be tracked using high throughput genomic approaches, Howell says, particularly in the regions associated with learning and memory. Sequencing technology allows Howell and his team to determine which mouse genes get altered in response to genetic variation, aging, diet and exercise, and to make precise comparisons to human aging and disease.
Emerging genomic engineering technologies, such as the CRISPR/Cas9 gene editing tool, are allowing researchers more precision in building mouse models that should be more predictive of Alzheimer’s disease, allowing for more accurate testing of potential therapies.
“We’re in the middle of a revolution in genomic research,” Howell says. “Two major things are happening. One is that we can very easily sequence many, many human genomes and identify variants that are causing disease or increasing susceptibility to disease. The second is our ability to precisely manipulate the mouse genome. At a rate not previously thought possible, we are identifying variants in humans, modeling the consequences in mice to understand exactly how changes in our genome increase our susceptibility for complex diseases like Alzheimer’s disease.”
Top 10 JAX stories of 2015
The top JAX stories of 2015
Biomedical science is capitalizing on various advances in tools and technology to explore and manipulate genomes. Three technologies in particular are transforming medicine: high-throughput genome sequencing, gene editing technology CRISPR, and single-cell genomics.
Structural deterioration associated with old age can be prevented by long-term aerobic exercise starting in mid-life, according to Jackson Laboratory Assistant Professor Gareth Howell (above), Associate Research Scientist Ileana Soto and their colleagues.
The team found that structural changes that make the blood–brain barrier leaky and result in inflammation of brain tissues in old mice can be mitigated by allowing the animals to run regularly, so providing a potential explanation for the beneficial effects of exercise on dementia in humans.
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