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Science 25 February 2005:
Vol. 307. no. 5713, pp. 1282 - 1288
DOI: 10.1126/science.1105681
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Research Articles

Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer's Disease

Gorazd B. Stokin,1 Concepción Lillo,2 Tomás L. Falzone,1 Richard G. Brusch,1 Edward Rockenstein,3 Stephanie L. Mount,1 Rema Raman,5 Peter Davies,6 Eliezer Masliah,3,4 David S. Williams,2,3 Lawrence S. B. Goldstein1*

We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-ß peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of ß-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.

1 Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
2 Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
3 Department of Neurosciences, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
4 Department of Pathology, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
5 Department of Family and Preventive Medicine, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
6 Department of Pathology, F526, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, NY 10461, USA.

* To whom correspondence should be addressed. E-mail: lgoldstein{at}ucsd.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)