Modulation of β-Amyloid Precursor Protein Processing by the Low Density Lipoprotein Receptor-related Protein (LRP)
Open accessAbstract
Beta-amyloid peptide (Abeta), which plays a central role in the pathogenesis of Alzheimer's disease, is derived from the transmembrane beta-amyloid precursor protein (APP) by proteolytic processing. Although mechanisms associated with Abeta generation are not fully understood, it is known that Abeta can be generated within endosomal compartments upon internalization of APP from the cell surface. The low density lipoprotein receptor-related protein (LRP) was previously shown to mediate the endocytosis of APP isoforms containing the Kunitz proteinase inhibitor domain (Kounnas, M. Z., Moir, R. D., Rebeck, G. W., Bush, A. I., Argraves, W. S., Tanzi, R. E., Hyman, B. T., and Strickland, D. K. (1995) Cell 82, 331-340; Knauer, M. F., Orlando, R. A., and Glabe, C. G. (1996) Brain Res. 740, 6-14). The objective of the current study was to test the hypothesis that LRP-mediated internalization of cell surface APP can modulate APP processing and thereby affect Abeta generation. Here, we show that long term culturing of cells in the presence of the LRP-antagonist RAP leads to increased cell surface levels of APP and a significant reduction in Abeta synthesis. Further, restoring LRP function in LRP-deficient cells results in a substantial increase in Abeta production. These findings demonstrate that LRP contributes to Abeta generation and suggest novel pharmacological approaches to reduce Abeta levels based on selective LRP blockade.
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Unlike LDLR, LRP1 is an APP binding protein that influences APP endocytic trafficking and cellular distribution such that processing to Aβ and its extracellular release is enhanced.
“For example, unlike LDLR, LRP1 is an APP binding protein that influences APP endocytic trafficking and cellular distribution such that processing to Aβ and its extracellular release is enhanced (Pietrzik et al., 2002; Ulery et al., 2000).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Ulery et al., 2000
The Discussion and the passage following Fig. 4 (pages not provided) report that functional LRP is associated with increased Aβ generation and secretion, and propose that APP–LRP interaction favors amyloidogenic processing by altering endocytic trafficking. The copy does not establish the contrast with LDLR, and presents the trafficking mechanism as a proposal rather than a demonstrated cause. (LLM, conf=0.85)
Experimental — accuracy not yet measuredLRP1 is known to increase production of Aβ peptide.
“Since LRP1 is known to increase the production of Aβ peptide (Ulery et al., 2000; Pietrzik et al., 2002), LRP1-deficient cell lines were chosen to eliminate any possible contribution of LRP1 to this process.”
From LRAD3, A Novel Low-Density Lipoprotein Receptor Family Member That Modulates Amyloid Precursor Protein Trafficking (2011) · cites this paper as Ulery et al., 2000
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References 45 · Cited by 271
Research works printed but not linked: 3
- Bu, G., Williams, S., Strickland, D. K., and Schwartz, A. L. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 7427-7431
- Citron, M., Diehl, T. S., Gordon, G., Biere, A. L., Seubert, P., and Selkoe, D. J. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 13170 -13175
- Van Nostrand, W. E., Farrow, J. S., Wagner, S. L., Bhasin, R., Goldgaber, D., Cotman, C. W., and Cunningham, D. D. (1991) Proc. Natl. Acad. Sci.
- Authors
- Ulery, P. G., Beers, J., Mikhailenko, I., Tanzi, R. E., Rebeck, G. W., Hyman, B. T., & Strickland, D. K.
- Affiliations
- American Red Cross (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Strickland, Dudley K.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-03
- Volume
- 275
- Issue
- 10
- Pages
- 7410-7415
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2058071886
- Cited by
- 271
- References
- 45
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 10 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 7 · 2019: 4 · 2018: 3 · 2017: 9 · 2016: 8 · 2015: 5 · 2014: 6 · 2013: 14 · 2012: 17
- FWCI
- 12.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG 12406)
- National Heart, Lung, and Blood Institute (HL50784, R01HL050784, HL-54710, P01HL054710)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid precursor protein, low density lipoprotein receptor-related protein, endocytosis, rap, Alzheimer's disease, APP processing
- MeSH terms
- Alzheimer Disease, Cells, Cultured, Humans, Receptors, Immunologic, Receptors, LDL, Amyloid beta-Protein Precursor, Low Density Lipoprotein Receptor-Related Protein-1
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