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The Journal of Neuroscience, June 20, 2007, 27(25):6771-6780; doi:10.1523/JNEUROSCI.5564-06.2007
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Neurobiology of Disease
Alzheimer's-Type Amyloidosis in Transgenic Mice Impairs Survival of Newborn Neurons Derived from Adult Hippocampal Neurogenesis
Laure Verret,1 * Joanna L. Jankowsky,2 * Guilian M. Xu,3 David R. Borchelt,3 andClaire Rampon1 1Centre National de la Recherche Scientifique, Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, 31062 Toulouse, France, 2Division of Biology, California Institute of Technology, Pasadena, California 91125, and 3Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610
Correspondence should be addressed to either of the following: Dr. Joanna L. Jankowsky, California Institute of Technology, M.C. 156-29, Pasadena, CA 91125, Email: jlj2{at}caltech.edu; or Dr. Claire Rampon, UMR5169 Centre National de la Recherche Scientifique, Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, 118, route de Narbonne, 31062 Toulouse Cedex 4, France, Email: rampon{at}cict.fr
Alzheimer's disease (AD) is characterized by severe neuronal loss in several brain regions important for learning and memory. Of the structures affected by AD, the hippocampus is unique in continuing to produce new neurons throughout life. Mounting evidence indicates that hippocampal neurogenesis contributes to the processing and storage of new information and that deficits in the production of new neurons may impair learning and memory. Here, we examine whether the overproduction of amyloid-ß (Aß) peptide in a mouse model for AD might be detrimental to newborn neurons in the hippocampus. We used transgenic mice overexpressing familial AD variants of amyloid precursor protein (APP) and/or presenilin-1 to test how the level (moderate or high) and the aggregation state (soluble or deposited) of Aß impacts the proliferation and survival of new hippocampal neurons. Although proliferation and short-term survival of neural progenitors in the hippocampus was unaffected by APP/Aß overproduction, survival of newborn cells 4 weeks later was dramatically diminished in transgenic mice with Alzheimer's-type amyloid pathology. Phenotypic analysis of the surviving population revealed a specific reduction in newborn neurons. Our data indicate that overproduction of Aß and the consequent appearance of amyloid plaques cause an overall reduction in the number of adult-generated hippocampal neurons. Diminished capacity for hippocampal neuron replacement may contribute to the cognitive decline observed in these mice.
Key words: hippocampal neurogenesis; Alzheimer's disease; dentate gyrus; transgenic mouse; amyloid precursor protein; presenilin 1
Received Dec. 22, 2006; revised May 9, 2007; accepted May 9, 2007.
Correspondence should be addressed to either of the following: Dr. Joanna L. Jankowsky, California Institute of Technology, M.C. 156-29, Pasadena, CA 91125, Email: jlj2{at}caltech.edu; or Dr. Claire Rampon, UMR5169 Centre National de la Recherche Scientifique, Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, 118, route de Narbonne, 31062 Toulouse Cedex 4, France, Email: rampon{at}cict.fr
This article has been cited by other articles:
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Neurogenesis and Alterations of Neural Stem Cells in Mouse Models of Cerebral Amyloidosis
Am. J. Pathol., June 1, 2008; 172(6): 1520 - 1528.
[Abstract] [Full Text] [PDF]
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