Introducing mutations within the amyloid precursor protein (APP) that affect β- and γ-secretase cleavages results in amyloid plaque formation in vivo. However, the relationship between β-amyloid deposition and the subcellular site of Aβ production is unknown. To determine the effect of increasing β-secretase (BACE) activity on Aβ deposition, we generated transgenic mice overexpressing human BACE. Although modest overexpression enhanced amyloid deposition, high BACE overexpression inhibited amyloid formation despite increased β-cleavage of APP. However, high BACE expression shifted the subcellular location of APP cleavage to the neuronal perikarya early in the secretory pathway. These results suggest that the production, clearance, and aggregation of Aβ peptides are highly dependent on the specific neuronal subcellular domain wherein Aβ is generated and highlight the importance of perikaryal versus axonal APP proteolysis in the development of Aβ amyloid pathology in Alzheimer's disease.
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17 January 2005
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January 10 2005
BACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo
Edward B. Lee,
Edward B. Lee
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
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Bin Zhang,
Bin Zhang
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
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Kangning Liu,
Kangning Liu
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
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Eric A. Greenbaum,
Eric A. Greenbaum
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
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Robert W. Doms,
Robert W. Doms
2Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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John Q. Trojanowski,
John Q. Trojanowski
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
3Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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Virginia M.-Y. Lee
Virginia M.-Y. Lee
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
3Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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Edward B. Lee
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
Bin Zhang
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
Kangning Liu
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
Eric A. Greenbaum
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
Robert W. Doms
2Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
John Q. Trojanowski
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
3Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Virginia M.-Y. Lee
1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
3Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Correspondence to Virginia M.-Y. Lee: [email protected]
Abbreviations used in this paper: AD, Alzheimer's disease; APP, amyloid precursor protein; BACE, β-secretase; FA, formic acid; IDE, insulin-degrading enzyme; NFM, molecular weight neurofilament subunit; PhAT, anti–phospho-APP-threonine 668; PrP, prion protein; Tg, transgenic.
Received:
July 12 2004
Accepted:
November 22 2004
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2005
J Cell Biol (2005) 168 (2): 291–302.
Article history
Received:
July 12 2004
Accepted:
November 22 2004
Citation
Edward B. Lee, Bin Zhang, Kangning Liu, Eric A. Greenbaum, Robert W. Doms, John Q. Trojanowski, Virginia M.-Y. Lee; BACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo . J Cell Biol 17 January 2005; 168 (2): 291–302. doi: https://doi.org/10.1083/jcb.200407070
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