With the help of BrightFocus funding, a research team headed by Catherine Kaczorowski, PhD, of Jackson Laboratory, has paved the way for a vast improvement in the way researchers study Alzheimer’s disease (AD). They have introduced a ‘real-world’ mix of genetic diversity into the standard mouse model.
Their accomplishment, which was published online in the journal Neuron on Dec. 27 (Neuner et al, 2018), is being hailed as a major breakthrough in the AD research world.
Kaczorowski is an associate professor and Evnin Family Chair in Alzheimer's Research at Jackson Laboratory, private research facility in Bar Harbor, ME. Lead author Sarah Neuner is a graduate student working in Dr. Kaczorowski’s lab, and one of the key personnel working on the BrightFocus project.
Jackson Laboratory officials asked BrightFocus, as one of the funding agencies, to comment on the work in a news release.
“Dr. Kaczorowski, and her colleagues are the first to produce mice that have genetic diversity similar to that present in the human population, which will enable her and other researchers to discover what is modifying the age of onset or increasing the risk of memory failure,” said Diane Bovenkamp, PhD, vice president of Scientific Affairs at BrightFocus Foundation.
“Alzheimer’s is an extremely complex disease, and one contributor to clinical trial failures may be that we aren’t testing drug candidates on models that accurately reflect the disease.
“BrightFocus is proud to be funding Dr. Kaczorowski’s innovative research, which has exciting potential for identifying future personalized, precision-medicine treatments.”
Project Started With a BrightFocus ADR Grant
In 2016, Dr. Kaczorowski received a 2016-19 BrightFocus Alzheimer’s Disease Research grant to identify “modifier” genes that may affect when, where, and how people begin to develop the symptoms of Alzheimer’s, and establish how these genes influence brain cell networks. The forward-thinking proposal reflected the understanding that AD behaves differently, even in individuals with similar genetic risks, based on how genetic and environmental factors interact. Among people with similar genetic risk for AD, some will be more resilient and able to resist developing AD symptoms, at least for a period of time. Gaining a better understanding of how they manage to preserve cognitive function could figure into new drugs and prevention strategies.
Back in 2016, Kaczorowski proposed to create “a panel of genetically diverse mice harboring causal familial AD mutations,” and to conduct experiments to measure how their varying genetic make-up affected the age at which they developed AD, how quickly its pathology spread, and the impact on their cognitive function and connectivity between key memory regions of the brain.
To accomplish this goal, Kaczorowski and team combined a well-established mouse model of familial AD (the “5XFAD” model) with a genetically diverse set of mice to create a new panel of “AD-BXD” mice that have a high degree of overlap with the genetic, molecular, pathologic, and cognitive features of AD in humans.
Now There’s Wider Backing from NIH
Starting in 2017, Kaczorowski’s research also received major funding from the National Institute of Aging (NIA), the branch of the National Institutes of Health with lead responsibility for Alzheimer’s research. Kaczorowski’s lab is one of 10 multidisciplinary and multi-institutional research teams supported by NIA’s newly established Resilience-Alzheimer's Disease Consortium (Resilience-AD) program.
NIH officials issued their own news release summarizing her work’s impact. "This is the first study to show that you can replicate many of the molecular features of Alzheimer's disease in a genetically diverse mouse model," said NIA Director Richard J. Hodes, MD, and that will help researchers make “better use of mouse models for precision medicine research – both basic and translational – for AD,” he said.
Indeed, being able to replicate in mice with AD the same type of genetic diversity seen in humans, and measure the impact of that on AD risk and resilience, “will enable the research community to learn a lot more about the complex nature of Alzheimer's a lot faster," added Suzana Petanceska, PhD, who oversees the Resilience-AD program as a program director in the NIA Division of Neuroscience.
This new combined animal model will be a beneficial tool to better understand the nature of AD and the molecular factors that contribute to and/or protect from the disease.
Making the Mouse More Relevant to Human AD
In recent years, the huge body of AD research that’s been conducted in mouse models has come under criticism for being too dissimilar from human disease to be able to draw useful parallels. Similarly, drugs first developed and tested in animal models have proven disappointing when tested in human subjects. Perhaps the reason may lie with lack of heterogeneity.
In contrast, Kaczorowski says her animal research has always been “informed by epidemiologic models,” and her own attempts to capture a “real world” picture of what’s happening. These attributes were part of her cross-disciplinary working environment at the University of Tennessee Health Science Center in Memphis, where she was based when she received her BrightFocus ADR grant, moving to Jackson Lab soon after.
Without heterogeneity, most mouse models of AD achieve a degree of similarity with human AD that hovers around 30 percent, Kaczorowski said, whereas “when you introduce genetic diversity, you find congruence with human sporadic AD goes up to 90 percent.”
At the recent Society for Neuroscience meeting last November, Kaczoroski was lead author or collaborator on a number of studies that use her new mouse model to look at such factors as the rate of sensorimotor decline and the impact of dietary modification in AD.
“I think genetic diversity is a big theme this year,” she said when interviewed at SfN.
And that’s just the beginning.
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