Human Molecular Genetics Advance Access originally published online on August 11, 2008
Human Molecular Genetics 2008 17(22):3474-3486; doi:10.1093/hmg/ddn240
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Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides
1 Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute 2 Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0683, USA 3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
* To whom correspondence should be addressed at: Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, 414 Leichtag Biomedical Research Building, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0683. Tel: +1 8585349700; Fax: +1 8585349701; Email: lgoldstein{at}ucsd.edu
Received June 15, 2008; Revised July 21, 2008; Accepted August 8, 2008
Overexpression of amyloid precursor protein (APP), as well as mutations in the APP and presenilin genes, causes rare forms of Alzheimer’s disease (AD). These genetic changes have been proposed to cause AD by elevating levels of amyloid-β peptides (Aβ), which are thought to be neurotoxic. Since overexpression of APP also causes defects in axonal transport, we tested whether defects in axonal transport were the result of Aβ poisoning of the axonal transport machinery. Because directly varying APP levels also alters APP domains in addition to Aβ, we perturbed Aβ generation selectively by combining APP transgenes in Drosophila and mice with presenilin-1 (PS1) transgenes harboring mutations that cause familial AD (FAD). We found that combining FAD mutant PS1 with FAD mutant APP increased Aβ42/Aβ40 ratios and enhanced amyloid deposition as previously reported. Surprisingly, however, this combination suppressed rather than increased APP-induced axonal transport defects in both Drosophila and mice. In addition, neuronal apoptosis induced by expression of FAD mutant human APP in Drosophila was suppressed by co-expressing FAD mutant PS1. We also observed that directly elevating Aβ with fusions to the Familial British and Danish Dementia-related BRI protein did not enhance axonal transport phenotypes in APP transgenic mice. Finally, we observed that perturbing Aβ ratios in the mouse by combining FAD mutant PS1 with FAD mutant APP did not enhance APP-induced behavioral defects. A potential mechanism to explain these findings was suggested by direct analysis of axonal transport in the mouse, which revealed that axonal transport or entry of APP into axons is reduced by FAD mutant PS1. Thus, we suggest that APP-induced axonal defects are not caused by Aβ.
Present address: Institute of Clinical Neurophysiology, Division of Neurology, University Medical Center, Zalo
ka cesta 7 and Gerontopsychiatric Unit, University Psychiatric Hospital, Studenec 48, SI-1000 Ljubljana, Slovenia.
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