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The Journal of Neuroscience, April 2, 2008, 28(14):3555-3566; doi:10.1523/JNEUROSCI.0208-08.2008

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Neurobiology of Disease
A Two-Year Study with Fibrillar β-Amyloid (Aβ) Immunization in Aged Canines: Effects on Cognitive Function and Brain Aβ

Elizabeth Head,^1,2 Viorela Pop,³ Vitaly Vasilevko,¹ MaryAnn Hill,¹ Tommy Saing,¹ Floyd Sarsoza,¹ Michaela Nistor,¹ Lori-Ann Christie,¹ Saskia Milton,⁴ Charles Glabe,^1,4 Edward Barrett,⁵ and David Cribbs^1,2

¹Institute for Brain Aging and Dementia, and Departments of ²Neurology, ³Neurobiology and Behavior, and ⁴Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697, and ⁵Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108

Correspondence should be addressed to Dr. Elizabeth Head, Institute for Brain Aging and Dementia, Department of Neurology, University of California, 1259 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4540. Email: ehead{at}uci.edu

Aged canines (dogs) accumulate human-type β-amyloid (Aβ) in diffuse plaques in the brain with parallel declines in cognitive function. We hypothesized that reducing Aβ in a therapeutic treatment study of aged dogs with preexisting Aβ pathology and cognitive deficits would lead to cognitive improvements. To test this hypothesis, we immunized aged beagles (8.4–12.4 years) with fibrillar Aβ_1–42 formulated with aluminum salt (Alum) for 2.4 years (25 vaccinations). Cognitive testing during this time revealed no improvement in measures of learning, spatial attention, or spatial memory. After extended treatment (22 vaccinations), we observed maintenance of prefrontal-dependent reversal learning ability. In the brain, levels of soluble and insoluble Aβ_1–40 and Aβ_1–42 and the extent of diffuse plaque accumulation was significantly decreased in several cortical regions, with preferential reductions in the prefrontal cortex, which is associated with a maintenance of cognition. However, the amount of soluble oligomers remained unchanged. The extent of prefrontal Aβ was correlated with frontal function and serum anti-Aβ antibody titers. Thus, reducing total Aβ may be of limited therapeutic benefit to recovery of cognitive decline in a higher mammalian model of human brain aging and disease. Immunizing animals before extensive Aβ deposition and cognitive decline to prevent oligomeric or fibrillar Aβ formation may have a greater impact on cognition and also more directly evaluate the role of Aβ on cognition in canines. Alternatively, clearing preexisting Aβ from the brain in a treatment study may be more efficacious for cognition if combined with a second intervention that restores neuron health.

Key words: beagle; executive function; memory; oligomers; reversal learning; spatial attention; visual discrimination learning

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Received Sept. 6, 2007; accepted Feb. 20, 2008.

Correspondence should be addressed to Dr. Elizabeth Head, Institute for Brain Aging and Dementia, Department of Neurology, University of California, 1259 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4540. Email: ehead{at}uci.edu

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