Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease |
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Authors: | Stokin Gorazd B Lillo Concepción Falzone Tomás L Brusch Richard G Rockenstein Edward Mount Stephanie L Raman Rema Davies Peter Masliah Eliezer Williams David S Goldstein Lawrence S B |
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Affiliation: | 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. |
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Abstract: | 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-beta peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of beta-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease. |
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