Scientists at the California National Primate Research Center (CNPRC) at the University of California, Davis, say they have developed a model of the early stages of Alzheimer’s disease in rhesus macaques. The macaque model, described in a paper (“A novel tau‐based rhesus monkey model of Alzheimer’s pathogenesis”) published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, could allow better testing of new treatments, according to the researchers.
“Alzheimer’s disease (AD) is a devastating condition with no effective treatments, with promising findings in rodents failing to translate into successful therapies for patients. Targeting the vulnerable entorhinal cortex (ERC), rhesus monkeys received two injections of an adeno‐associated virus expressing a double tau mutation (AAV‐P301L/S320F) in the left hemisphere, and control AAV‐green fluorescent protein in the right ERC. Noninjected aged‐matched monkeys served as additional controls,” wrote the investigators.
“Within three months we observed evidence of misfolded tau propagation, similar to what is hypothesized to occur in humans. Viral delivery of human 4R‐tau also coaptates monkey 3R‐tau via permissive templating. Tau spreading is accompanied by robust neuroinflammatory response driven by TREM2+ microglia, with biomarkers of inflammation and neuronal loss in the cerebrospinal fluid and plasma.
“These results highlight the initial stages of tau seeding and propagation in a primate model, a more powerful translational approach for the development of new therapies for AD.”
The model was developed by the lab of John Morrison, PhD, director and core scientist at the CNPRC, in collaboration with Jeffrey Kordower, PhD, the Alla V. Solomon Jesmer professor of neurological sciences, Rush University Medical Center, and Paramita Chakrabarty, PhD, assistant professor at the University of Florida.
Alzheimer’s disease is thought to be caused by misfolding of the tau and amyloid proteins. Misfolded proteins spread through the brain, leading to inflammation and cell death. Tau protein is commonly found in neurons of the brain and central nervous system, but not elsewhere.
Researchers think that decades may elapse between the silent beginnings of the disease and the first signs of cognitive decline. Understanding what happens over these years could be key to preventing or reversing symptoms of Alzheimer’s disease. But it is difficult to study therapeutic strategies without a powerful animal model that resembles the human condition as closely as possible, Morrison said.
Much research has focused on transgenic mice that express a human version of amyloid or tau proteins, but these studies have proven difficult to translate into new treatments.
New translational models needed
Humans and monkeys have two forms of the tau protein in their brains, but rodents only have one, said Danielle Beckman, PhD, postdoctoral researcher at the CNPRC and first author on the paper.
“We think the macaque is a better model, because it expresses the same versions of tau in the brain as humans do,” she explained.
Mice also lack a prefrontal cortex, a region of the human brain that is highly vulnerable to Alzheimer’s disease. Prefrontal cortex is present in rhesus macaques and critically important for cognitive functions in both humans and monkeys. There is a need for new and better animal models for Alzheimer’s disease that can stand between mouse models and human clinical trials, according to Beckman.
Chakrabarty and colleagues created versions of the human tau gene with mutations that would cause misfolding, wrapped in a virus particle. These vectors were injected into rhesus macaques (into the entorhinal cortex). Within three months, they could see that misfolded tau proteins had spread to other parts of the animal’s brains. They found misfolding both of the introduced human mutant tau protein and of the monkey’s own tau proteins.
“The pattern of spreading demonstrated unequivocally that tau-based pathology followed the precise connections of the entorhinal cortex and that the seeding of pathological tau could pass from one region to the next through synaptic connections,” Morrison said. “This capacity to spread through brain circuits results in the damage to cortical areas responsible for higher level cognition quite distant from the entorhinal cortex.”
The same team has previously established spreading of misfolded amyloid proteins in macaques, representing the early stages of Alzheimer’s disease, by injecting short pieces of faulty amyloid. The new tau protein model likely represents a middle stage of the disease, noted Beckman, adding that “we think that this represents a more degenerative phase, but before widespread cell death occurs.”
The researchers next plan to test if behavioral changes comparable to human Alzheimer’s disease develop in the rhesus macaque model. If so, it could be used to test therapies that prevent misfolding or inflammation.
“We have been working to develop these models for the last four years,” said Morrison. “I don’t think you could do this without a large collaborative team and the extensive resources of a National Primate Research Center.”