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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aged
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Aged, 80 and over
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism*
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Alzheimer Disease / pathology*
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Axonal Transport*
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Axons / pathology*
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Axons / physiology
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Basal Nucleus of Meynert / pathology
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Brain / metabolism*
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Brain / pathology*
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Cells, Cultured
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Cytoplasmic Vesicles / ultrastructure
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Female
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Hippocampus
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Humans
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Kinesins / metabolism
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Male
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Neurons / metabolism
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Organelles / ultrastructure
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Plaque, Amyloid / pathology
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Time Factors
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Microtubule-Associated Proteins
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Kinesins