28 May 2008

Humans are unique in many ways, but susceptibility to Alzheimer disease pathology may no longer be one of them. While some animals get amyloid plaques and a limited degree of tau deposition, no other species has been found to naturally recapitulate the two major hallmarks of AD—plaques and neurofibrillary tangles. That is, until now. In the May 14 Journal of Comparative Neurology, researchers at Yerkes National Primate Center, Atlanta, Georgia, report that Jeanie, a 41-year-old chimpanzee who died from natural causes, had amyloid deposits and tau pathology that included paired-helical filaments—heretofore thought to occur only in humans. The results indicate that humans are not the only primates susceptible to Alzheimer’s pathology. And yet we are the only primates to get AD. “This issue of a uniquely human susceptibility to Alzheimer’s disease is one reason we are interested in non-human primates,” said senior author Lary Walker in an interview with ARF. “We hope that by analyzing everything—from the lesions that occur in the brains of the primates to genetics—we might be able to find a clue as to why humans have this tendency and primates don’t. That in a nutshell is the significance of this sort of work.” How long these efforts can continue is unclear, however, given that there is a growing reluctance to fund research on chimpanzees, and a legislative push to outlaw even the type of non-invasive, observational work on chimpanzees and other great apes that Walker and colleagues perform.

In contrast to small monkeys such as rhesus macaques, which also develop amyloid deposits, chimpanzees and other great apes are used almost exclusively for observational research. Jeanie had been living at the Yerkes field station in a group of other chimps for about 30 years. She died shortly after showing signs of acute paralysis. An autopsy confirmed she had had a massive stroke. On postmortem, first author Rebecca Rosen and colleagues looked for signs of AD-related markers. That’s when they noticed the tau pathology. “We’ve looked at some chimps before and it is not unusual to see an occasional tau immunoreactive neuron or even a cluster of neurites, but this was really very striking,” said Walker. Rosen and colleagues found tau pathology throughout Jeanie’s cortex and in some subcortical regions. Lesions included tau-laden neurons, neuropil threads, and diverse plaque-like structures. The prefrontal cortex was most affected, followed by the temporal and occipital lobes. Subcortical structures with tau pathology included the globus pallidus, neostriatum, diencephalon, and occasionally the white matter. The tau lesions reacted with antibodies typically used to characterize tau pathology in human brain (including AT8, CP13 ,and MC1), and when the researchers looked at the structures in the electron microscope, they found bundles of paired helical filaments that are identical in size and helical periodicity (160 nm) to those found in humans. Surprisingly, there was little tau pathology in the hippocampus, with only an occasional tau-immunoreactive neuron in the CA field. “If this were incipient AD, we would expect the hippocampus to show much more tauopathy,” said Walker.

Jeanie also had cerebral amyloid angiopathy (CAA), which has been previously documented in chimpanzees. The CAA was moderate and extended to both sides of the brain. She also had much higher levels of both Aβ42 and Aβ40 in the brain than found in human AD cases. Walker cautioned that brain damage can upregulate amyloid precursor protein expression, so the elevated Aβ could have been an acute response, perhaps to the stroke. The CAA was indeed slightly more severe in the left hemisphere where the stroke occurred, but the two are probably not related since Jeanie’s stroke was ischemic and it is hemorrhagic stroke that has been linked to CAA. Stroke is a risk factor for AD, as is high serum cholesterol and obesity. Jeanie had all three, though her obesity was moderate. Whether these risk factors contributed to her elevated Aβ and tau pathology is not clear, but Walker noted that an MRI taken 10 years prior showed that Jeanie’s brain at that time had looked perfectly normal, indicating that any ongoing ischemia was not present throughout her adult life. It is unlikely that her stroke was the cause of the CAA or tau deposits, since she died within hours of the ischemic event and these pathologies take longer to build up.

Though Jeanie had not been cognitively tested, the care staff at Yerkes reported no indication that she was cognitively impaired in any way. Apparently chimpanzees can have the pathologic hallmarks of Alzheimer’s without any overt signs of disease. It is not clear why, but the answer may be of importance to studying the human condition. “There are certain things about normal human biology that come into much sharper focus when you compare humans to our closest relative,” suggested Todd Preuss, a co-author on the paper. “If we lose the chimpanzees, if they go extinct, or if the legislation is so restrictive that we cannot do the same study in chimpanzees that we do in humans, we will lose something tremendously valuable in terms of our ability to understand human biology,” Preuss said.

Those three scenarios are currently playing out. Yerkes, for example, has stopped breeding chimpanzees, partly because the cost of raising a chimp to the ripe old age of 40 or 50 years can reach into the hundreds of thousands of dollars per animal. Simultaneously, chimps face increasing pressure in their natural habitat, increasing their risk of extinction. “It may well be that in 50 years the only chimps left are those in captivity,” said Preuss. That raises conservation issues, since around 1,000 chimpanzees are necessary for a self-sustaining colony, and there may be only 2,000 in all of the U.S. at present. On the legislative front, a bill has been introduced in Congress that would force relocation of great apes to retirement sanctuaries and ban any invasive procedures on them. For this bill’s purpose, the term “invasive” includes drawing blood or administering anesthesia, which is needed for neuroimaging. Similar legislation has been passed or is under consideration in Europe.

Joseph Erwin started the Great Ape Aging Project (GAAP) when he directed the Division of Neurobiology, Behavior, and Genetics at BIOQUAL, a company that provides accredited facilities for intramural NIH investigators. He was curator of primates for the Chicago Zoological Society's Brookfield Zoo and scientific advisor to the Ape Taxon Advisory Group (Ape-TAG) of the Association for Zoos and Aquariums (AZA). Erwin believes that this legislation is poorly thought out. “I think the way it is written, it is not sufficiently protective of great apes and at the same time erroneously protective of great apes,” he told ARF. Its purpose appears to be not primarily to protect great apes but to simply keep them out of research, he suggested. “There are times when it would be a good idea to do an MRI of a great ape when it is not absolutely clinically required, but it could benefit the individual or other members of the species. To be absolutely prohibited from sedating an animal for that reason is not protective,” Erwin said.

Erwin started GAAP together with Daniel Perl, chief neuropathologist at Mount Sinai Medical Center, New York. The project has enlisted the help of zoos to help preserve postmortem tissue. GAAP currently has tissue samples for more than 100 great apes, and the effort has already led to some interesting findings. Erwin and colleagues identified von Economo neurons (VENs) in great apes (Nimchinsky et al., 1999). These large projection neurons reside in the anterior cingulate cortex and are absent in smaller primates. They are believed to play a crucial role in self-awareness and are lost in large numbers in AD (see Nimchinsky et al., 1995). Even more intriguingly, perhaps, these neurons have recently been implicated in the loss of social and emotional functions that are characteristic of behavioral variant frontotemporal dementia, a tauopathy (Seeley et al., 2007; see also Seeley et al., 2006; Viskontas et al., 2007).

Walker agrees that it is important to learn as much as possible about chimpanzees while we still can. “I think it is good for us, and I think it is good for them,” he said. There are some ongoing initiatives that may help protect chimpanzees, which by some current projections will be gone from the wild by 2030. The joint University of San Diego/SALK Center for Academic Research and Training in Anthropogeny (CARTA), co-directed by Ajit Varki, plans to study the origins of human evolution using chimpanzees for comparison, and the National Chimpanzee Observatory and Great Ape Zoological Gardens in Louisiana has an ambitious project to help preserve chimpanzees by providing a safe, natural habitat. These initiatives plan to study chimpanzees in a non-invasive manner. On a final note, this is different research from transgenic manipulations that are sometimes performed on smaller primates such as macaques (see ARF related news story).—Tom Fagan

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References

News Citations

1. Monkey Genetics: Transgenic Rhesus With Huntington Disease 21 May 2008

Paper Citations

1. Nimchinsky EA, Gilissen E, Allman JM, Perl DP, Erwin JM, Hof PR. A neuronal morphologic type unique to humans and great apes. Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5268-73. PubMed.
2. Nimchinsky EA, Vogt BA, Morrison JH, Hof PR. Spindle neurons of the human anterior cingulate cortex. J Comp Neurol. 1995 Apr 24;355(1):27-37. PubMed.
3. Seeley WW, Allman JM, Carlin DA, Crawford RK, Macedo MN, Greicius MD, Dearmond SJ, Miller BL. Divergent social functioning in behavioral variant frontotemporal dementia and Alzheimer disease: reciprocal networks and neuronal evolution. Alzheimer Dis Assoc Disord. 2007 Oct-Dec;21(4):S50-7. PubMed.
4. Seeley WW, Carlin DA, Allman JM, Macedo MN, Bush C, Miller BL, Dearmond SJ. Early frontotemporal dementia targets neurons unique to apes and humans. Ann Neurol. 2006 Dec;60(6):660-7. PubMed.
5. Viskontas IV, Possin KL, Miller BL. Symptoms of frontotemporal dementia provide insights into orbitofrontal cortex function and social behavior. Ann N Y Acad Sci. 2007 Dec;1121:528-45. PubMed.

External Citations

1. bill has been introduced

Further Reading

News

1. Monkey Genetics: Transgenic Rhesus With Huntington Disease 21 May 2008