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Cited by 140Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

BACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo

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Lee, Edward B., Zhang, Bin, Liu, Kangning, Greenbaum, Eric A., Doms, Robert W., Trojanowski, John Q., Lee, Virginia M.-Y.·2005·The Journal of Cell Biology
DOI 10.1083/jcb.200407070PMC PMC2171598
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Abstract

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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  • BACE1 overexpression in Tg2576 mice causes Aβ production to shift from the axonal compartment to the somatodendritic compartment, reducing steady-state Aβ levels and plaque deposition.

    “Lee et al. (2005) have shown that 𝛃 -site APP-cleaving enzyme 1 (BACE1) overexpression in Tg2576 mice causes A 𝛃 production to shift from the axonal compartment to the somatodendritic compartment in which it is efficiently degraded, thus reducing steady-state A 𝛃 levels and plaque deposition.”

    From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Lee et al., 2005

    The Discussion (page unavailable) says BACE overexpression shifted APP processing from axons and terminals toward neuronal cell bodies, and the Results report reduced steady-state Aβ and reduced deposition at higher BACE expression. But the Discussion presents enhanced degradation as one possible explanation, not an established mechanism; the Results also report increased cortical deposition in the lowest-overexpression line. (LLM, conf=0.87)

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Authors
Lee, E. B., Zhang, B., Liu, K., Greenbaum, E. A., Doms, R. W., Trojanowski, J. Q., & Lee, V. M.-Y.
Affiliations
  • 1The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
  • University of Pennsylvania (US)
ORCID
Venue
The Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2005-01-10
Volume
168
Issue
2
Pages
291-302
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.200407070
PMC
PMC2171598
OpenAlex
W2139599612
Cited by
140
References
3
Citations by year
2026: 1 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 2 · 2017: 5 · 2016: 8 · 2015: 8 · 2014: 4 · 2013: 8 · 2012: 10
FWCI
9.63
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Cell Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (P01AG011542, T32 AG 00255, AG 11542, T32AG000255)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
beta-secretase, amyloid precursor protein, amyloid-beta deposition, transgenic mice, Alzheimer's disease, amyloid plaques, APP mutations, secretory pathway
MeSH terms
Alzheimer Disease, Animals, Axons, Brain, Brain Chemistry, Cerebellum, Cerebral Cortex, Female, Hippocampus, Humans, Ligation, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Optic Nerve, Endopeptidases, Phosphorylation, Prions, Sciatic Nerve, Spinal Cord, Gene Expression Regulation, Enzymologic, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Protein Transport, Immunoprecipitation, Mice, Amyloid Precursor Protein Secretases, Plaque, Amyloid

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