Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides.
Open accessAbstract
The beta-amyloid or beta/A4 peptides that accumulate as filamentous aggregates in the extracellular space of Alzheimer disease (AD) brains are derived from one or more alternatively spliced amyloid precursor proteins (APPs). The more abundant APPs in the central nervous system are the 695-(APP695), 751- (APP751), and 770- (APP770) amino acid isoforms, and each could be the source of beta/A4 peptide that accumulates in the AD brain. It is plausible that altered metabolism of these APPs by central nervous system neurons could lead to the release and deposition of beta/A4 peptide in brain parenchyma. Thus, we examined the expression and processing of the three major brain APPs in nearly pure human neurons (NT2N cells) derived from a teratocarcinoma cell line (NTera2/c1.D1 or NT2 cells) after retinoic acid treatment. NT2N neurons expressed almost exclusively APP695, whereas NT2 cells expressed predominantly APP751/770. Furthermore, the processing of the APPs in NT2N cells was distinct from NT2 and nonneuronal cells. Most significantly, the NT2N neurons but not the NT2 cells constitutively generated intracellular beta/A4 peptide and released it into the culture medium. This work demonstrates the intracellular production of beta/A4 peptide and suggests that cultured NT2N cells may provide a unique model system for understanding the contribution of neurons and APP695 to amyloidogenesis in the AD brain.
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Cites
The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987) · Nature · doi:10.1038/325733a0 · Cited by 4,619 · see citing works
Amyloid β-peptide is produced by cultured cells during normal metabolism
Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B. L., Lieberburg, I., Koo, E. H., Schenk, D., Teplow, D. B., et al. (1992) · Nature · doi:10.1038/359322a0 · Cited by 1,921 · see citing works
Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., & Selkoe, D. J. (1992) · Nature · doi:10.1038/360672a0 · Cited by 1,757 · see citing works
Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids
Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., Sinha, S., Schiossmacher, M., Whaley, J., Swindlehurst, C., et al. (1992) · Nature · doi:10.1038/359325a0 · Cited by 1,731 · see citing works
Production of the Alzheimer Amyloid β Protein by Normal Proteolytic Processing
Shoji, M., Golde, T. E., Ghiso, J., Cheung, T. T., Estus, S., Shaffer, L. M., Cai, X.-D., McKay, D. M., Tintner, R., Frangione, B., et al. (1992) · Science · doi:10.1126/science.1439760 · Cited by 1,447 · see citing works
Self-citationGoldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U., & Gajdusek, D. C. (1987) · Science · doi:10.1126/science.3810169 · Cited by 1,333 · see citing works
Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein
Weidemann, A., König, G., Bunke, D., Fischer, P. Q., Salbaum, J. M., Masters, C. L., & Beyreuther, K. T. (1989) · Cell · doi:10.1016/0092-8674(89)90177-3 · Cited by 1,233 · see citing works
Tanzi, R. E., McClatchey, A. I., Lamperti, E. D., Villa‐Komaroff, L., Gusella, J. F., & Neve, R. L. (1988) · Nature · doi:10.1038/331528a0 · Cited by 1,093 · see citing works
Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity
Kitaguchi, N., Takahashi, Y., Tokushima, Y., Shiojiri, S., & Ito, H. (1988) · Nature · doi:10.1038/331530a0 · Cited by 1,083 · see citing works
A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors
Ponte, P. A., Gonzalez‐DeWhitt, P. A., Schilling, J., Miller, J., Hsu, D. K., Greenberg, B., Davis, K. L., Wallace, W., Lieberburg, I. M., Fuller, F. H., et al. (1988) · Nature · doi:10.1038/331525a0 · Cited by 1,050 · see citing works
Release of Excess Amyloid β Protein from a Mutant Amyloid β Protein Precursor
Cai, X.-D., Golde, T. E., & Younkin, S. G. (1993) · Science · doi:10.1126/science.8424174 · Cited by 913 · see citing works
Self-citationHaass, C., Koo, E., Mellon, A., Hung, A. Y., & Selkoe, D. (1992) · Nature · doi:10.1038/357500a0 · Cited by 901 · see citing works
Katzman, R. (1986) · New England Journal of Medicine · doi:10.1056/nejm198604103141506 · Cited by 801 · see citing works
Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport.
Koo, E. H., Sisodia, S. S., Archer, D. R., Martin, L. J., Weidemann, A., Beyreuther, K., Fischer, P., Masters, C. L., & Price, D. L. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.4.1561 · Cited by 733 · see citing works
Processing of the amyloid protein precursor to potentially amyloidogenic derivatives.
Golde, T., Estus, S., Younkin, L., Selkoe, D., & Younkin, S. (1992) · Science · doi:10.1126/science.1738847 · Cited by 710 · see citing works
Self-citationAndrews, P. W. (1984) · Developmental Biology · doi:10.1016/0012-1606(84)90316-6 · Cited by 670 · see citing works
Andrews, P. W., Damjanov, I., Simón, D., Banting, G. S., Carlin, C. R., Dracopoli, N. C., & Fogh, J. M. (1984) · PubMed · Cited by 613 · see citing works
Pleasure, S., Page, C., & Lee, V. (1992) · Journal of Neuroscience · doi:10.1523/jneurosci.12-05-01802.1992 · Cited by 607 · see citing works
Self-citationSelkoe, D. J., Podlisny, M. B., Joachim, C. L., Vickers, E., Lee, G. S., Fritz, L. C., & Oltersdorf, T. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.19.7341 · Cited by 579 · see citing works
Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide
Seubert, P. A., Oltersdorf, T., Lee, M., Barbour, R., Blomquist, C. L., Davis, D. L., Bryant, K., Fritz, L. C., Galasko, D., Thal, L. J., et al. (1993) · Nature · doi:10.1038/361260a0 · Cited by 552 · see citing works
Lee, V., Carden, M. J., Schlaepfer, W. W., & Trojanowski, J. Q. (1987) · Journal of Neuroscience · doi:10.1523/jneurosci.07-11-03474.1987 · Cited by 490 · see citing works
Self-citationOltersdorf, T., Fritz, L. C., Schenk, D. B., Lieberburg, I. M., Johnson‐Wood, K., Beattie, E. C., Ward, P. J., Blacher, R. W., Dovey, H. F., & Sinha, S. (1989) · Nature · doi:10.1038/341144a0 · Cited by 457 · see citing works
Golde, T. E., Estus, S., Usiak, M., Younkin, L. H., & Younkin, S. G. (1990) · Neuron · doi:10.1016/0896-6273(90)90100-t · Cited by 431 · see citing works
Self-citationPotentially Amyloidogenic, Carboxyl-Terminal Derivatives of the Amyloid Protein Precursor
Estus, S., Golde, T. E., Kunishita, T., Blades, D. A., Lowery, D. E., Eisen, M., Usiak, M., QU, X., Tabira, T., Greenberg, B., et al. (1992) · Science · doi:10.1126/science.1738846 · Cited by 431 · see citing works
Self-citationDyrks, T., Weidemann, A., Multhaup, G., Salbaum, J. M., Lemaire, H.-G., Kang, J., Müller‐Hill, B., Masters, C. L., & Beyreuther, K. T. (1988) · The EMBO Journal · doi:10.1002/j.1460-2075.1988.tb02900.x · Cited by 394 · see citing works
Expression of the Alzheimer amyloid precursor gene transcripts in the human brain
Neve, R. L. (1988) · Neuron · doi:10.1016/0896-6273(88)90166-3 · Cited by 388 · see citing works
Haass, C., Hung, A. Y., & Selkoe, D. J. (1991) · Journal of Neuroscience · doi:10.1523/jneurosci.11-12-03783.1991 · Cited by 278 · see citing works
Lee, V., & Andrews, P. W. (1986) · Journal of Neuroscience · doi:10.1523/jneurosci.06-02-00514.1986 · Cited by 245 · see citing works
Self-citationKang, J., & Müller‐Hill, B. (1990) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(90)90992-v · Cited by 185 · see citing works
Hung, A. Y., Koo, E. H., Haass, C., & Selkoe, D. J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.20.9439 · Cited by 175 · see citing works
Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor
Yoshikawa, K., Aizawa, T., & Hayashi, Y. (1992) · Nature · doi:10.1038/359064a0 · Cited by 173 · see citing works
Arai, H., Lee, V. M. ‐., Messinger, M. L., Greenberg, B., Lowery, D. E., & Trojanowski, J. Q. (1991) · Annals of Neurology · doi:10.1002/ana.410300509 · Cited by 163 · see citing works
Self-citationFukuchi, K.-I., Kamino, K., Deeb, S. S., et al. (1992) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(05)80126-3 · Cited by 82 · see citing works
Molecular features of hypothalamic plaques in Alzheimer's disease.
Standaert, D. G., Lee, V. M.-Y., Greenberg, B., Lowery, D. E., & Trojanowski, J. Q. (1991) · PubMed Central · Cited by 62 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Intracellular amyloid-β in Alzheimer's disease
LaFerla, F. M., Green, K. N., & Oddo, S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2168 · Cited by 1,942 · see citing works
Billings, L. M., Oddo, S., Green, K. N., McGaugh, J. L., & LaFerla, F. M. (2005) · Neuron · doi:10.1016/j.neuron.2005.01.040 · Cited by 1,294 · see citing works
Wang, J., Dickson, D. W., Trojanowski, J. Q., & Lee, V. M.-Y. (1999) · Experimental Neurology · doi:10.1006/exnr.1999.7085 · Cited by 567 · see citing works
Self-citationThe Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice
LaFerla, F. M., Tinkle, B. T., Bieberich, C. J., Haudenschild, C. C., & Jay, G. (1995) · Nature Genetics · doi:10.1038/ng0195-21 · Cited by 513 · see citing works
Oxidative stress increases expression and activity of BACE in NT2 neurons
Tamagno, E., Bardini, P., Obbili, A., Vitali, A., Borghi, R., Zaccheo, D., Pronzato, M. A., Danni, O., Smith, M. A., Perry, G., et al. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0515 · Cited by 385 · see citing works
Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease
Gouras, G. K., Tampellini, D., Takahashi, R. H., & Capetillo-Zarate, E. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0679-9 · Cited by 372 · see citing works
Intraneuronal Aβ accumulation and origin of plaques in Alzheimer's disease
Gouras, G. K., Almeida, C. G., & Takahashi, R. H. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.05.022 · Cited by 338 · see citing works
Wirths, O., Multhaup, G., Czech, C., Blanchard, V., Moussaoui, S., Tremp, G., Pradier, L., Beyreuther, K., & Bayer, T. A. (2001) · Neuroscience Letters · doi:10.1016/s0304-3940(01)01876-6 · Cited by 336 · see citing works
Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease
Baranello, R., Bharani, K., Padmaraju, V., Chopra, N., Lahiri, D., Greig, N., Pappolla, M., & Sambamurti, K. (2015) · Current Alzheimer Research · doi:10.2174/1567205012666141218140953 · Cited by 331 · see citing works
Skovronsky, D. M., Doms, R. W., & Lee, V. M.-Y. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.141.4.1031 · Cited by 290 · see citing works
Self-citationLord, A., Kalimo, H., Eckman, C., Zhang, X.-Q., Lannfelt, L., & Nilsson, L. N. G. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.12.007 · Cited by 260 · see citing works
Borg, J.-P., Yang, Y., De Taddéo-Borg, M., Margolis, B., & Turner, R. S. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.24.14761 · Cited by 201 · see citing works
Self-citationTurner, R. S., Suzuki, N., Chyung, A. S. C., Younkin, S. G., & Lee, V. M.-Y. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.15.8966 · Cited by 161 · see citing works
Self-citationWirths, O., Multhaup, G., Czech, C., Feldmann, N., Blanchard, V., Tremp, G., Beyreuther, K., Pradier, L., & Bayer, T. A. (2002) · Brain Pathology · doi:10.1111/j.1750-3639.2002.tb00442.x · Cited by 125 · see citing works
Distinct Pools of β-Amyloid in Alzheimer Disease–Affected Brain: A Clinicopathologic Study
Steinerman, J. R., Irizarry, M., Scarmeas, N., Raju, S., Brandt, J., Albert, M., Blacker, D., Hyman, B., & Stern, Y. (2008) · Archives of Neurology · doi:10.1001/archneur.65.7.906 · Cited by 104 · see citing works
Role of amyloid beta in lipid homeostasis
Grösgen, S., Grimm, M. O. W., Frieß, P., & Hartmann, T. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.05.002 · Cited by 90 · see citing works
Brännström, K., Öhman, A., Nilsson, L., Pihl, M., Sandblad, L., & Olofsson, A. (2014) · Journal of the American Chemical Society · doi:10.1021/ja503535m · Cited by 74 · see citing works
Gouras, G. K., Willén, K., & Tampellini, D. (2012) · Life Sciences · doi:10.1016/j.lfs.2012.06.004 · Cited by 39 · see citing works
- Authors
- Wertkin, A. M., Turner, R. S., Pleasure, S. J., Golde, T. E., Younkin, S. G., Trojanowski, J. Q., & Lee, V. M.
- Affiliations
- University of Pennsylvania (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1993-10-15
- Volume
- 90
- Issue
- 20
- Pages
- 9513-9517
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC47599
- OpenAlex
- W2061798362
- Cited by
- 231
- References
- 34
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 1 · 2023: 5 · 2022: 2 · 2021: 2 · 2020: 7 · 2019: 2 · 2018: 8 · 2017: 6 · 2015: 3 · 2014: 6 · 2013: 5 · 2012: 12
- FWCI
- 10.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG-09215)
- National Institute on Aging (AG09215, AG06656, P01AG009215, R01AG006656)
- 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
- amyloid precursor protein, APP695, APP751, APP770, amyloid-beta, Alzheimer's disease, amyloidogenesis, neuronal differentiation, retinoic acid, APP processing, cultured neurons
- MeSH terms
- Cell Differentiation, Glycosylation, Humans, Neurons, Protein Processing, Post-Translational, RNA, Messenger, Tretinoin, Tumor Cells, Cultured, Gene Expression, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Teratocarcinoma
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