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The Journal of Neuroscience, June 29, 2005, 25(26):6213-6220; doi:10.1523/JNEUROSCI.0664-05.2005
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Neurobiology of Disease
Treatment with an Amyloid- Antibody Ameliorates Plaque Load, Learning Deficits, and Hippocampal Long-Term Potentiation in a Mouse Model of Alzheimer's Disease
Richard E. Hartman,1,2
Yukitoshi Izumi,2
Kelly R. Bales,3
Steven M. Paul,3
David F. Wozniak,2 and
David M. Holtzman1
Departments of 1Neurology and 2Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, and 3Neuroscience Discovery Research, Eli Lilly and Company, Indianapolis, Indiana 46285
PDAPP transgenic mice overexpress a mutant form of human amyloid precursor protein under control of the platelet-derived growth factor promoter in CNS neurons that causes early onset, familial Alzheimer's disease in humans. These mice, on a mixed genetic background, have been shown to have substantial learning impairments from early ages, as well as an age-dependent decline in learning ability that has been hypothesized to be caused by amyloid- (A) accumulation. The goals of this study were to determine: (1) whether PDAPP mice on a pure C57BL/6 background develop more severe age-dependent learning deficits than wild-type mice; (2) if so, whether A accumulation accounts for the excessive decline in learning ability; and (3) whether the learning deficits are reversible, even after significant A deposition. At 4-6, 10-12, or 17-19 months of age, PDAPP and littermate wild-type mice on a C57BL/6 background were tested on a 5 week water maze protocol in which the location of the escape platform changed weekly, requiring the mice to repeatedly learn new information. PDAPP mice exhibited impaired spatial learning as early as 4 months (pre-A deposition), and the performance of both wild-type and PDAPP mice declined with age. However, PDAPP mice exhibited significantly greater deterioration with age. Direct evidence for the role of A accumulation in the age-related worsening in PDAPP mice was provided by the observation that systemic treatment over several weeks with the anti-A antibody 10D5 reduced plaque deposition, increased plasma A, improved hippocampal long-term potentiation, and improved behavioral performance in aged PDAPP mice with substantial A burden.
Key words: APP; amyloid; spatial; immunization; electrophysiology; neuropathology
Received Feb 18, 2005;
revised April 16, 2005;
accepted May 24, 2005.
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