The newest possible model to test therapeutics and interventions for neurodegenerative diseases could be a 20-year-old baboon.
A team at Texas Biomedical Research Institute’s Southwest National Primate Research Center (SNPRC) took the first steps in developing the baboon as an appropriate animal model for early stage Alzheimer’s disease, finding a steep age-related cognitive decline in baboons about 20-years-old, which is the equivalent of a 60-year-old human. According to the lead researcher Dr. Marcel Daadi, Texas Biomed SNPRC Associate Professor and the lead researcher on the study, this is the first time a naturally-occurring model for early-stage Alzheimer’s has been reported.
Daadi and colleagues published their findings in a paper titled “Age-related Cognitive Decline in Baboons: Modeling the Prodromal Phase of Alzheimer’s Disease and Related Dementias” in the May issue of Aging.
“We don’t know how Alzheimer’s disease starts, and if you are trying to treat a patient already with advanced disease, it is nearly impossible to treat them because of the significant loss in brain cells” Daadi said in a statement. “If we detect early on pathology in the brain then we can target interventions to prevent it from progressing, and we are in a better position to help.
He added: “This model could be relevant to test promising drugs, to better understand how and why the disease develops and to study the areas of the brain affected in order to determine how can we impact these pathways.”
In the past, lab model testing for neurodegenerative diseases’ therapeutic interventions has been rodents. However, while mice have been integral to a better understanding of neurodegenerative diseases, they haven’t proven as effective in translating promising therapies.
Daadi’s team explored the possibility of a baboon model because of primates are much more comparable to humans in terms of genetics, physiology, cognition, emotion and social behavior. Humans and nonhuman primates (NHP) share many similarities, including age-dependent changes in gene expression and a decline in neural and immune functions.
“The failure rate in clinical trials of Alzheimer’s disease therapeutics is extremely high at about 99.6%, and we need to change that,” Daadi said.
Previous studies have pinpointed the prefrontal cortex (PFC) of the brain as one of the regions most affected by age. The PFC plays an important role in working memory function, self-regulatory and goal-directed behaviors, which are all vulnerable to aging.
To observe whether these PFC functions are impacted by aging in baboons and determine whether the baboons at varying ages could discern and learn new tasks, Daadi and his team separated the baboons into two groups based on age (adult group and aged group). Four cognitive tests were performed to observe novel learning, motor function and memory and shape association.
“What we found is that aged baboons lagged significantly in performance among all four tests for attention, learning and memory” Daadi said. “The delay or inability to collect rewards (response latency) also increased in older baboons, suggesting a decline in motivation and/or motor skills. The team then used a more complex task requiring integration of several cognitive processes and demonstrated that aged subjects actually have deficiencies in attention, learning and memory. Human studies have suggested a precipitous decline in brain systems function and cognition with 60 years as the potential breakpoint. These findings are consistent with our results.”
The research center tackled the contentious question of why they use animals in testing: “While some research questions may adequately be addressed using cell cultures, tissue studies or computer models, which we also employ, research with animals continues to be critical for the advancement of human health. Disease processes are typically complex, involving multiple physiological processes and multiple organ systems that simply require the use of nonhuman primate models.”
2,500 nonhuman primates — including 1,100 baboons — live on the research campus. Nearly all of them live in groups, spending much of their time playing and grooming in a rich social environment. They also participate in “enrichment programs” designed to help stimulate species-typical behaviors and promote psychological well-being using social, physical, occupational, feeding and sensory enrichment techniques that often mimic natural behaviors seen in the wild.
They also help with important research on infectious diseases with some research on chronic diseases like heart disease, diabetes, liver disease, and neurological disorders. The SNPRC is a resource for scientists across the U.S. who are working on research around chronic diseases, autoimmune disorders, neurological disorders and more.
Recent studies with premature baboons enabled Texas Biomed researchers to refine the technique of high-frequency oscillatory ventilation, which is used to save the lives of thousands of premature babies and minimize lung damage in these children.
“Virtually every major advance in medical knowledge and treatment has involved research using animal models. Animal research has saved lives, extended life expectancy, and improved the quality of life for both humans and animals by enabling scientists to conduct critical experiments that identified ways to prevent, treat, and cure disease.”
Nonhuman primates are have also provided valuable insight into the development of the hepatitis B and C vaccines, Ebola virus, and into the impact of the Zika virus on mothers and children.
Daadi and his team plan to submit a National Institutes of Health grant to allow for further research on the baboon as a model for Alzheimer’s research. Early detection of age-associated cognitive dysfunction is critical — and it could may an understanding of the breakdown of brain systems and help lead to better interventions.
“Our next step is to investigate the neuropathologies behind this cognitive decline and perform imaging to understand what happens to the neural connections and determine where defects may be,” he said. “We will also look at biomarkers that can give us an idea of why this steep decline is happening. All this data will enable us to further characterize the baboon as a naturally-occurring model that may prove useful for testing early therapeutic interventions.”