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The Journal of Neuroscience, May 25, 2005, 25(21):5217-5224; doi:10.1523/JNEUROSCI.5080-04.2005
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Neurobiology of Disease
Environmental Enrichment Mitigates Cognitive Deficits in a Mouse Model of Alzheimer's Disease
Joanna L. Jankowsky,1
Tatiana Melnikova,1,2
Daniel J. Fadale,4
Guilian M. Xu,1
Hilda H. Slunt,1
Victoria Gonzales,1
Linda H. Younkin,4
Steven G. Younkin,4
David R. Borchelt,1,3 and
Alena V. Savonenko1,2
Departments of 1Pathology, 2Neurology, and 3Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and 4Mayo Clinic Jacksonville, Jacksonville, Florida 32224
Epidemiological studies suggest that individuals with greater education or more cognitively demanding occupations have diminished risk of developing dementia. We wanted to test whether this effect could be recapitulated in rodents using environmental enrichment, a paradigm well documented to attenuate behavioral deficits induced by various pathological insults. Here, we demonstrate that learning and memory deficits observed in a transgenic mouse model of Alzheimer's disease can be ameliorated by enrichment. Female transgenic mice overexpressing amyloid precursor protein and/or presenilin-1 and nontransgenic controls were placed into enriched or standard cages at 2 months of age and tested for cognitive behavior after 6 months of differential housing. Enrichment significantly improved performance of all genotypes in the radial water maze and in the classic and repeated-reversal versions of the Morris water maze. However, enrichment did not benefit all genotypes equally. Mice overproducing amyloid- (A), particularly those with amyloid deposits, showed weaker memory for the platform location in the classic Morris water maze and learned new platform positions in the repeated-reversals task less quickly than their nontransgenic cagemates. Nonetheless, enrichment normalized the performance of A-overproducing mice to the level of standard-housed nontransgenic mice. Moreover, this functional preservation occurred despite increased neuritic plaque burden in the hippocampus of double-transgenic animals and elevated steady-state A levels, because both endogenous and transgene-derived A are increased in enriched animals. These results demonstrate that the generation of A in vivo and its impact on the function of the nervous system can be strongly modulated by environmental factors.
Key words: Alzheimer's disease; transgenic mouse; amyloid precursor protein; A; environmental enrichment; cognitive behavior
Received Dec 13, 2004;
revised April 14, 2005;
accepted April 17, 2005.
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