17 Oct 2014

Mouse models of Alzheimer’s fail to capture many aspects of human disease. Might monkeys do a better job? In the October 8 Journal of Neuroscience, researchers led by Fernanda De Felice at the Federal University of Rio de Janeiro, make a case for using them. The authors injected Aβ oligomers into the brains of middle-aged macaques and, one month later, detected numerous features of AD pathology, including synapse loss, inflammation, and tau phosphorylation. In particular, the authors saw evidence of neurofibrillary tangles, a hallmark of Alzheimer’s that rodent models fail to recapitulate unless they express mutant tau. “That we can reproduce most of the key aspects of Alzheimer’s in a short time may allow us to test therapeutics in a primate model,” De Felice suggested.

Primate and human brains share structural and functional similarities. Like people, macaques typically do not develop amyloid plaques until late in life, age 25 to 30 for these primates, making them impractical as natural disease models (see Podlisny et al., 1991; Oikawa et al., 2010). In a previous study, Changiz Geula at Northwestern University, Chicago, and Bruce Yankner at Harvard Medical School, Boston, generated a macaque model by injecting fibrillar Aβ into aged monkeys. This approach stimulated tau phosphorylation and neuronal death, but no neurofibrillary tangles (see Geula et al., 1998). Because many researchers now believe that oligomeric Aβ exerts more toxicity than fibrillar, De Felice and colleagues wondered if injecting oligomers might better model the disease.

First author Leticia Forny-Germano oligomerized synthetic Aβ42 in vitro according to the method of co-author William Klein at Northwestern University, Evanston, Illinois (see Lambert et al., 1998). She injected 100 μg of these preparations every three days for three weeks into the lateral ventricles of four cynomolgus (also known as crab-eating) macaques between 9 and 16 years old. Three control animals received sham injections. One week after injections ended, the authors sacrificed the animals and analyzed the brains for pathology.

Injected macaques did not develop plaques, but accumulated the injected oligomeric Aβ in neurons of numerous brain regions, including the entorhinal cortex, hippocampus, amygdala, striatum, and frontal cortex. Other regions, such as midbrain and cerebellum, remained relatively free of Aβ. This pattern matches that seen in human disease, and suggests that certain brain regions are more vulnerable than others, De Felice noted. She believes that the pattern is not simply due to ease of diffusion, since some areas near the ventricles accumulated few oligomers, while oligomers piled up in some distant regions. Perhaps certain neurons possess a receptor complex that recognizes the oligomers, she speculated.

The authors saw activation of microglia and astrocytes in affected brain regions. As in human AD, synapses deteriorated. At autopsy, electron microscopy revealed a 15 percent drop in these structures compared to control animals, while levels of pre- and post-synaptic markers plummeted by 60 percent in injected brains.

Tau pathology mushroomed in the injected macaques. Phosphorylation at several amino acids shot up by four times or more. In addition, the authors report structures they call tau tangles in neurons using antibodies that recognize aggregated forms of the protein. Under an electron microscope, these structures had a fibrillar appearance. “They look very similar to what we see in Alzheimer’s brains,” De Felice said. For comparison, the authors injected rats with oligomeric Aβ using the same protocol. Tau phosphorylation increased, but no neurofibrillary tangles appeared in the rodents.

Do injected macaques also develop cognitive and behavioral changes? To answer this, co-author Douglas Munoz at Queen’s University, Kingston, Ontario, Canada, will evaluate cognitive decline in the animals using a version of the CANTAB cognitive test battery.

Other researchers called the model promising, but noted that it needs further characterization. In particular, they wanted additional studies on the tau aggregates to confirm that they represent bona fide neurofibrillary tangles. Researchers have noted that electron microscopy often picks up fibrillar structures in cells that are unrelated to tau. Higher resolution electron microscopy could clarify the presence of fibrils, and these samples should also be labeled with a tubulin antibody to distinguish fibrils from microtubules, Yankner suggested.

Yankner was intrigued by what the authors did not find. “The authors see no evidence for neuronal cell loss, which is a striking absence in view of all these other pathological features,” Yankner said. The answer may lie in the relatively young age of injected monkeys. In Yankner’s previous study, he found that neurons died in old monkeys that received fibrillar Aβ injections, but not in younger animals, suggesting that older brains may be more vulnerable to neuron loss. Since Alzheimer’s patients lose massive numbers of neurons, older macaques might model the disease even more closely, he speculated.—Madolyn Bowman Rogers

 

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References

Paper Citations

1. Podlisny MB, Tolan DR, Selkoe DJ. Homology of the amyloid beta protein precursor in monkey and human supports a primate model for beta amyloidosis in Alzheimer's disease. Am J Pathol. 1991 Jun;138(6):1423-35. PubMed.
2. Oikawa N, Kimura N, Yanagisawa K. Alzheimer-type tau pathology in advanced aged nonhuman primate brains harboring substantial amyloid deposition. Brain Res. 2010 Feb 22;1315:137-49. PubMed.
3. Geula C, Wu CK, Saroff D, Lorenzo A, Yuan M, Yankner BA. Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat Med. 1998 Jul;4(7):827-31. PubMed.
4. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. PubMed.

Further Reading

News

1. Chimpanzees Get AD Pathology—But Clock Is Ticking on Research 28 May 2008
2. Green News Flash—Sustainable Primate Models on the Horizon 29 May 2009
3. Watching Adult Neurogenesis—In Primates It Takes Time 11 Jun 2011
4. What Primates Can Tell Us About Normal Brain Aging 29 Jul 2011
5. Honolulu: Monkey, Rat Join Menagerie of Mammalian AD Models 11 Aug 2010
6. Aging Primates—Brain Iron Up, Motor Skills and Plastic Synapses Down 9 Jul 2010