Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease.
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.
Stokin
Gorazd B
GB
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.
Lillo
Concepción
C
Falzone
Tomás L
TL
Brusch
Richard G
RG
Rockenstein
Edward
E
Mount
Stephanie L
SL
Raman
Rema
R
Davies
Peter
P
Masliah
Eliezer
E
Williams
David S
DS
Goldstein
Lawrence S B
LS
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport; D001369:Axons / Q000473:pathology* / Q000502:physiology; D020532:Basal Nucleus of Meynert / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D022162:Cytoplasmic Vesicles / Q000648:ultrastructure; D005260:Female; D006624:Hippocampus; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D015388:Organelles / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000473:pathology; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008869:Microtubule-Associated Proteins; D016547:Kinesins