Research Brief: Combination Therapy Does the Trick for Old Dogs

Maybe you can teach old dogs new tricks—and reduce their amyloid-β burden. In the July 21 Journal of Neuroscience, researchers led by Carl Cotman at the University of Irvine, California, report a synergistic effect of environmental enrichment and antioxidants on reducing amyloid-β load in the brains of aged beagles. “The findings are not at all what we expected when we started this study,” Cotman told ARF. The finding hints that in humans, too, combination therapy might work better than monotherapies, which, in the case of antioxidants like vitamins C and E, have proved unable to stave off impending dementia.

Like humans, dogs are naturally susceptible to amyloid-β pathology, developing diffuse and dense core plaques as they age. Older dogs also start losing their smarts. This may be a reflection of Aβ accumulation or of other ongoing pathologies that are associated with age-related dementia, such as neuron loss, cortical atrophy, and poor neurogenesis, all of which have been documented in aging canines. Previously, Cotman and colleagues found that a combination of antioxidant supplementation and environmental enrichment prevents cognitive decline in older beagles and works better than either therapy alone (see Milgram et al., 2005). But it was not clear how the therapy worked.

Now, first author Viorela Pop and colleagues report that in aging beagles, the combination therapy reduces plaque load and soluble Aβ in the brain. There is even a hint of an effect on Aβ oligomers, which are now widely believed to be the most toxic forms of the peptide. However, the researchers found no correlation between any individual Aβ measure and cognitive performance. “The findings add to the accumulating data coming out of transgenic mice studies indicating that effects on Aβ do not correlate with change in cognitive function,” said Nicole Berchtold, one of the authors on the paper. “It seems that looking at amyloid is not necessarily the best endpoint.”

Cotman and colleagues ran their experiments on aging beagles very much like a human clinical trial. Not all beagles are as smart as their cartoon avatars would have us believe, so the researchers took baseline cognitive assessments and then randomized the dogs into groups with similar mean sagacity. One group served as a control, two others received either monotherapy, and the fourth group the combination. The antioxidant supplement included vitamins E and C, L-carnitine, and α-lipoic acid. The environmental enrichment included social (shared caging), physical (two 20-minute outdoor walks per week), environmental (availability of toys), and cognitive (20-30-minute testing per day) stimulation. The eight- to 12-year-old animals, eight per group, were treated for 2.69 years.

At the end of the trial, animals treated with antioxidants had reduced plaque burden in their brain. This was further reduced in the animals that received both interventions. In animals that received the antioxidant, Aβ plaques were predominantly diffuse, rather than the dense-core plaques associated with more advanced pathology. “It could be that the treatments are slowing plaque evolution and in that way helping maintain neuronal health,” suggested Berchtold.

How the treatments slow plaque development is not clear, but the researchers did find that levels of soluble Aβ42 were lower in dogs treated with the combination therapy than in any of the other three groups. This reduction was limited to the prefrontal cortex, however. There was also a trend toward lower levels of a 56 kDA soluble oligomer (detected with the A11 antibody developed by Charlie Glabe), which may be similar to Aβ*56, a toxic species identified in mice by Karen Ashe’s group (see ARF related news story). In keeping with the idea that the combination therapy reduced production of Aβ, dogs that received both treatments had more α-secretase activity in the parietal cortex, suggesting a shift toward non-amyloidogenic processing of APP.

While the reduction in brain amyloid may be welcome news, it did not herald any change in cognition. The researchers previously found that dogs on the combination therapy improved performance in a range of cognitive measures, including spatial memory, discrimination errors, and discrimination reversal errors. None of these measures correlated with any Aβ measure, including plaque load, soluble Aβ levels, number of oligomers, or α-secretase activity. “These dogs are like humans and show great variability in cognitive performance when they age, but when you look at things that correlate to that, amyloid is not a dependent variable,” said Cotman. A previous Aβ immunization study in dogs, supports this idea, since the immunotherapy lowered brain Aβ load but had little effect on cognition (see ARF related news story).

Nonetheless, the dual therapy profoundly improved canine cognition (see Milgram et al., 2005), and the additive effect suggests that multiple mechanisms may be involved. “This is one of the evolving lines of research that suggest there are other important targets besides Aβ,” said Cotman. He noted that markers of oxidative damage do correlate with behavior in dogs treated with the combined therapy, which boosts canine BDNF as well (see Fahnestock et al., 2010), and he suggested that multidomain treatments may be a valuable approach in humans. “Unfortunately, combination therapies have been outside the boundaries because the group size gets too big, there are too many variables, and getting funding to do multivariate interventions is hard, and that is a shame,” he said.—Tom Fagan

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References

News Citations

  1. Aβ Star is Born? Memory Loss in APP Mice Blamed on Oligomer
  2. Immunotherapy: Old Dogs, New Tricks

Paper Citations

  1. Milgram NW, Head E, Zicker SC, Ikeda-Douglas CJ, Murphey H, Muggenburg B, Siwak C, Tapp D, Cotman CW. Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study. Neurobiol Aging. 2005 Jan;26(1):77-90. PubMed.
  2. Fahnestock M, Marchese M, Head E, Pop V, Michalski B, Milgram WN, Cotman CW. BDNF increases with behavioral enrichment and an antioxidant diet in the aged dog. Neurobiol Aging. 2012 Mar;33(3):546-54. PubMed.

Further Reading

Primary Papers

  1. Pop V, Head E, Hill MA, Gillen D, Berchtold NC, Muggenburg BA, Milgram NW, Murphy MP, Cotman CW. Synergistic effects of long-term antioxidant diet and behavioral enrichment on beta-amyloid load and non-amyloidogenic processing in aged canines. J Neurosci. 2010 Jul 21;30(29):9831-9. PubMed.

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