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

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          Abstract

          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.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          2 April 2008
          : 28
          : 14
          : 3555-3566
          Affiliations
          [1] 1Institute for Brain Aging and Dementia, and
          [2]Departments of 2Neurology,
          [3] 3Neurobiology and Behavior, and
          [4] 4Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697, and
          [5] 5Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108
          Author notes
          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. ehead@ 123456uci.edu
          Article
          PMC6671080 PMC6671080 6671080 3335716
          10.1523/JNEUROSCI.0208-08.2008
          6671080
          18385314
          96b99f5e-e6ce-4f68-a40a-21539aa7d35c
          Copyright © 2008 Society for Neuroscience 0270-6474/08/283555-12$15.00/0
          History
          : 6 September 2007
          : 20 February 2008
          Categories
          Articles
          Neurobiology of Disease

          oligomers,beagle,reversal learning,memory,visual discrimination learning,executive function,spatial attention

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