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P4–098: In vivo turnover of retrogradely transported proteins by autophagy is impaired in PS/APP transgenic mice
Author(s) -
Lee Sooyeon,
Yang Dun-Sheng,
Kumar Asok,
Levy Efrat,
Hassinger Linda,
Cataldo Anne M.,
Nixon Ralph A.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1836
Subject(s) - neurite , endocytic cycle , microbiology and biotechnology , horseradish peroxidase , genetically modified mouse , vacuole , axoplasmic transport , autophagy , extracellular , immunostaining , chemistry , biology , transgene , biochemistry , in vitro , immunohistochemistry , immunology , endocytosis , apoptosis , gene , cytoplasm , cell , enzyme
Autophagy, a major pathway for protein and organelle turnover, is induced in neurons as a critical survival response in Alzheimer’s disease (AD). Autophagic vacuoles (AVs), which are capable of generating amyloid-beta, peptide (Yu et al., JCB, 2005), massively accumulate within dystrophic neurites. The significance of these AV accumulations for neurite regeneration or degeneration and their capacity for protein degradation are still unclear. Objective: We investigated in PS/ APP transgenic mice in vivo whether AVs in dystrophic neurites can still interact with endocytic and lysosomal compartments undergoing transport and efficiently degrade proteins. Methods/Results: We used endocytic uptake of native horseradish peroxidase (HRP) after brief intraventricular infusion in wild-type and PS/APP mice to track the dendritic transport and fate of endocytic vesicles in vivo over time (5-240 min). In sections of perfusion-fixed brains analyzed by EM, HRP was detected mainly extracellularly at 5 minutes post-infusion but by 1 hour, was principally intracellular, appearing along dendrites within numerous small ( 100nm) endocytic vesicles. In PS/APP mice, HRP also appeared by 1 hour in the large (0.5-2.0 microns) AVs accumulated within dystrophic neurites as well as in the extracellular space specifically around these neurites. By 4 hours, HRP had largely disappeared from small endocytic vesicles in dendrites of wild-type mice and was principally in rare lipofuscin granules in perikarya, suggesting relatively rapid turnover. By contrast, HRP was still detected within many AVs in dystrophic neurites of PS/APP mice, although HRP distribution within AVs and changes in the maturation states of HRP -containing AVs suggested a continued, albeit slowed, autophagic degradative process. Conclusions: Vesicular trafficking and fusion events within dystrophic neurites remain remarkably dynamic. Endocytic vesicles translocate along dendrites and either fuse with, or are sequestered by, autophagosomes accumulated within the dystrophic neurite. Compared to the highly efficient autophagy in normal neurons, however, autophagic protein degradation in dystrophic neurites of PS/APP mice is inefficient. The highly active transport of APP-rich organelles, continued fusion with AVs in dystrophic neurites, and delays in the complete lysosomal elimination by autophagic substrates provide highly favorable conditions for amyloidbeta, peptide production at these sites.