Inhibition of APP Trafficking by Tau Protein Does Not Increase the Generation of Amyloid‐β Peptides
Open accessAbstract
Amyloid‐β, a peptide derived from the precursor protein APP, accumulates in the brain and contributes to the neuropathology of Alzheimer's disease. Increased generation of amyloid‐β might be caused by axonal transport inhibition, via increased dwell time of APP vesicles and thereby higher probability of APP cleavage by secretase enzymes residing on the same vesicles. We tested this hypothesis using a neuronal cell culture model of inhibited axonal transport and by imaging vesicular transport of fluorescently tagged APP and β‐secretase (BACE1). Microtubule‐associated tau protein blocks vesicle traffic by inhibiting the access of motor proteins to the microtubule tracks. In neurons co‐transfected with CFP‐tau, APP‐YFP traffic into distal neurites was strongly reduced. However, this did not increase amyloid‐β levels. In singly transfected axons, APP‐YFP was transported in large tubules and vesicles moving very fast (on average 3 µm/s) and with high fluxes in the anterograde direction (on average 8.4 vesicles/min). By contrast, BACE1‐CFP movement was in smaller tubules and vesicles that were almost 2× slower (on average 1.6 µm/s) with ~18× lower fluxes (on average 0.5 vesicles/min). Two‐colour microscopy of co‐transfected axons confirmed that the two proteins were sorted into distinct carriers. The results do not support the above hypothesis. Instead, they indicate that APP is transported on vesicles distinct from the secretase components and that amyloid‐β is not generated in transit when transport is blocked by tau.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
APP is transported down both axons and dendrites.
“APP is transported down both axons and dendrites and Aβ appears to be generated preferentially at synapses [25, 54, 85].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [54]
Aβ appears to be generated preferentially at synapses.
“APP is transported down both axons and dendrites and Aβ appears to be generated preferentially at synapses [25, 54, 85].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [54]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4
LAEMMLI, U. K. (1970) · Nature · doi:10.1038/227680a0 · Cited by 249,961 · see citing works
Lounging in a lysosome: the intracellular lifestyle of Coxiella burnetii
Voth, D. E., & Heinzen, R. A. (2007) · Cellular Microbiology · doi:10.1111/j.1462-5822.2007.00901.x · Cited by 11,773 · see citing works
Schägger, H., & von Jagow, G. (1987) · Analytical Biochemistry · doi:10.1016/0003-2697(87)90587-2 · Cited by 11,420 · see citing works
Alzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063 · see citing works
A simplified system for generating recombinant adenoviruses
He, T., Zhou, S., da Costa, L. T., Yu, J., Kinzler, K. W., & Vogelstein, B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2509 · Cited by 3,209 · see citing works
APP Processing and Synaptic Function
Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S., & Malinow, R. (2003) · Neuron · doi:10.1016/s0896-6273(03)00124-7 · Cited by 1,644 · see citing works
Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer’s Disease
Stokin, G. B., Lillo, C., Falzone, T. L., Brusch, R. G., Rockenstein, E., Mount, S. L., Raman, R., Davies, P., Masliah, E., Williams, D. S., et al. (2005) · Science · doi:10.1126/science.1105681 · Cited by 1,214 · see citing works
Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
Ehehalt, R., Keller, P., Haass, C., Thiele, C., & Simons, K. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200207113 · Cited by 1,103 · see citing works
Self-citationStamer, K., Vogel, R., Thies, E., Mandelkow, E., & Mandelkow, E.-M. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200108057 · Cited by 885 · see citing works
Self-citationEbneth, A., Godemann, R., Stamer, K., Illenberger, S., Trinczek, B., Mandelkow, E.-M., & Mandelkow, E. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.143.3.777 · Cited by 820 · see citing works
Self-citationγ-Secretase-mediated proteolysis in cell-surface-receptor signalling
Fortini, M. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm910 · Cited by 818 · see citing works
Kamal, A., Almenar-Queralt, A., LeBlanc, J. F., Roberts, E. A., & Goldstein, L. S. B. (2001) · Nature · doi:10.1038/414643a · Cited by 583 · see citing works
Take five—BACE and the γ‐secretase quartet conduct Alzheimer's amyloid β‐peptide generation
Haass, C. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600061 · Cited by 547 · see citing works
Self-citationKamal, A., Stokin, G. B., Yang, Z., Xia, C.-H., & Goldstein, L. S. B. (2000) · Neuron · doi:10.1016/s0896-6273(00)00124-0 · Cited by 544 · see citing works
Matlin, K. S., & Simons, K. (1983) · Cell · doi:10.1016/0092-8674(83)90154-x · Cited by 508 · see citing works
Sastre, M., Steiner, H., Fuchs, K. P., Capell, A., Multhaup, G., Condron, M. M., Teplow, D. B., & Haass, C. (2001) · EMBO Reports · doi:10.1093/embo-reports/kve180 · Cited by 472 · see citing works
Self-citationAPP processing is regulated by cytoplasmic phosphorylation
Lee, M.-S., Kao, S.-C., Lemere, C. A., Xia, W., Tseng, H.-C., Zhou, Y., Neve, R. L., Ahlijanian, M. K., & Tsai, L. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200301115 · Cited by 457 · see citing works
Oligomerization of Alzheimer's β-Amyloid within Processes and Synapses of Cultured Neurons and Brain
Takahashi, R. H., Almeida, C. G., Kearney, P. F., Yu, F., Lin, M. T., Milner, T. A., & Gouras, G. K. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.5167-03.2004 · Cited by 445 · see citing works
A SIMPLE AND EFFICIENT METHOD FOR PURIFICATION OF INFECTIOUS RECOMBINANT ADENOVIRUS
Kanegae, Y., Makimura, M., & Saito, I. (1994) · Japanese Journal of Medical Science and Biology · doi:10.7883/yoken1952.47.157 · Cited by 444 · see citing works
Oligomers on the Brain: the Emerging Role of Soluble Protein Aggregates in Neurodegeneration.
Walsh, D. M., & Selkoe, D. J. (2004) · Protein and Peptide Letters · doi:10.2174/0929866043407174 · Cited by 428 · see citing works
Association of γ-Secretase with Lipid Rafts in Post-Golgi and Endosome Membranes
Vetrivel, K. S., Cheng, H., Lin, W., Sakurai, T., Li, T., Nukina, N., Wong, P. C., Xu, H., & Thinakaran, G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407986200 · Cited by 413 · see citing works
Maturation and Endosomal Targeting of β-Site Amyloid Precursor Protein-cleaving Enzyme
Huse, J. T., Pijak, D. S., Leslie, G. J., Lee, V. M.-Y., & Doms, R. W. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004175200 · Cited by 402 · see citing works
Avoidance of posterior tectal membranes by temporal retinal axons
Walter, J., Henke‐Fahle, S., & Bonhoeffer, F. (1987) · Development · doi:10.1242/dev.101.4.909 · Cited by 370 · see citing works
Rat Hippocampal Neurons in Low-Density Culture
Goslin, K., Asmussen, H., & Banker, G. A. (1998) · The MIT Press eBooks · doi:10.7551/mitpress/4913.003.0020 · Cited by 364 · see citing works
Neuronal membrane cholesterol loss enhances amyloid peptide generation
Abad‐Rodríguez, J., Ledesma, M. D., Craessaerts, K., Perga, S., Medina, M., Delacourte, A., Dingwall, C., Strooper, B. D., & Dotti, C. G. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200404149 · Cited by 329 · see citing works
Lazarov, O., Lee, M., Peterson, D. A., & Sisodia, S. S. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-22-09785.2002 · Cited by 302 · see citing works
Sisodia, S., Koo, E., Hoffman, P., Perry, G. L., & Price, D. (1993) · Journal of Neuroscience · doi:10.1523/jneurosci.13-07-03136.1993 · Cited by 284 · 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
Self-citationMultiple Assembly Pathways Underlie Amyloid-β Fibril Polymorphisms
Goldsbury, C. S., Frey, P., Olivieri, V., Aebi, U., & Müller, S. A. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.07.029 · Cited by 273 · see citing works
Self-citationPhosphorylation Regulates Intracellular Trafficking of β-Secretase
Walter, J., Fluhrer, R., Hartung, B., Willem, M., Kaether, C., Capell, A., Lammich, S., Multhaup, G., & Haass, C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011116200 · Cited by 272 · see citing works
Self-citationKaether, C., Skehel, P., & Dotti, C. G. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.4.1213 · Cited by 270 · see citing works
Self-citationBuxbaum, J. D., Thinakaran, G., Koliatsos, V. E., O’Callahan, J., Slunt, H. H., Price, D. L., & Sisodia, S. S. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09629.1998 · Cited by 266 · see citing works
Single-molecule investigation of the interference between kinesin, tau and MAP2c
Seitz, A., Kojima, H., Oiwa, K., Mandelkow, E.-M., Song, Y.-H., & Mandelkow, E. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf503 · Cited by 257 · see citing works
Self-citationMARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons
Mandelkow, E.-M., Thies, E., Trinczek, B., Biernat, J., & Mandelkow, E. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200401085 · Cited by 236 · see citing works
Self-citationGoing new places using an old MAP: tau, microtubules and human neurodegenerative disease
Garcia, M. L., & Cleveland, D. W. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00172-1 · Cited by 235 · see citing works
Axonal Transport, Amyloid Precursor Protein, Kinesin-1, and the Processing Apparatus: Revisited
Lazarov, O., Morfini, G. A., Lee, E. B., Farah, M. H., Szodorai, A., DeBoer, S. R., Koliatsos, V. E., Kins, S., Lee, V. M. ‐., Wong, P. C., et al. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3089-04.2005 · Cited by 221 · see citing works
Wacker, I. U., Kaether, C., Krömer, A., Migala, A., Almers, W., & Gerdes, H. (1997) · Journal of Cell Science · doi:10.1242/jcs.110.13.1453 · Cited by 206 · see citing works
Self-citationHerreman, A., Gassen, G. V., Bentahir, M., Nyabi, O., Craessaerts, K., Mueller, U., Annaert, W. G., & Strooper, B. D. (2003) · Journal of Cell Science · doi:10.1242/jcs.00292 · Cited by 195 · see citing works
Strooper, B. D., Simons, M., Multhaup, G., LEUVEN, F. V., Beyreuther, K. T., & Dotti, C. G. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00176.x · Cited by 176 · see citing works
Kaether, C., Schmitt, S., Willem, M., & Haass, C. (2006) · Traffic · doi:10.1111/j.1600-0854.2006.00396.x · Cited by 148 · see citing works
Self-citationBACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo
Lee, E. B., Zhang, B., Liu, K., Greenbaum, E. A., Doms, R. W., Trojanowski, J. Q., & Lee, V. M.-Y. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200407070 · Cited by 140 · see citing works
Principles of cargo attachment to cytoplasmic motor proteins
Kamal, A., & Goldstein, L. S. B. (2002) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(01)00295-2 · Cited by 133 · see citing works
Sheng, J. G., Price, D. L., & Koliatsos, V. E. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-22-09794.2002 · Cited by 124 · see citing works
Morin, P. J., Abraham, C. R., Amaratunga, A., Johnson, R. J., Huber, G., Sandell, J. H., & Fine, R. E. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb02147.x · Cited by 104 · see citing works
Defective kinesin heavy chain behavior in mouse kinesin light chain mutants
Rahman, A., Kamal, A., Roberts, E. A., & Goldstein, L. S. B. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.146.6.1277 · Cited by 102 · see citing works
The presenilin C‐terminus is required for ER‐retention, nicastrin‐binding and γ‐secretase activity
Kaether, C., Capell, A., Edbauer, D., Winkler, E., Novak, B., Steiner, H., & Haass, C. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600478 · Cited by 102 · see citing works
Self-citationIkin, A. F., Annaert, W. G., Takei, K., Camilli, P. V. D., Jahn, R., Greengard, P., & Buxbaum, J. D. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.50.31783 · Cited by 83 · see citing works
Human BACE Forms Dimers and Colocalizes with APP
Schmechel, A., Strauß, M., Schlicksupp, A., Pipkorn, R., Haass, C., Bayer, T. A., & Multhaup, G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402785200 · Cited by 77 · see citing works
Self-citationA lipid boundary separates APP and secretases and limits amyloid β-peptide generation
Kaether, C., & Haass, C. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200410090 · Cited by 75 · see citing works
Self-citationSplice variants of the β-site APP-cleaving enzyme BACE1 in human brain and pancreas
Ehehalt, R., Michel, B., Tonelli, D. D. P., Zacchetti, D., Simons, K., & Keller, P. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)00169-9 · Cited by 64 · see citing works
Self-citationA novel mechanism for the regulation of amyloid precursor protein metabolism
Chen, Q., Kimura, H., & Schubert, D. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200110151 · Cited by 63 · see citing works
Sheng, J. G., Price, D. L., & Koliatsos, V. E. (2003) · Experimental Neurology · doi:10.1016/j.expneurol.2003.08.018 · Cited by 58 · see citing works
Amaratunga, A., & Fine, R. E. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.29.17268 · Cited by 44 · see citing works
A Cargo Receptor Mystery APP arently Solved?
Sisodia, S. S. (2002) · Science · doi:10.1126/science.1069661 · Cited by 26 · see citing works
Petite, D., & Calvet, M.-C. (1995) · Brain Research · doi:10.1016/0006-8993(94)01269-n · Cited by 13 · see citing works
Zhao, Z., Ksiȩżak-Reding, H., Wang, J., et al. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.02.067 · Cited by 7 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Sisodia SS. Biomedicine. A cargo receptor mystery APParently solved? Science 2002;295:805-807.
Cited by
Sorted by citations
Trafficking and Proteolytic Processing of APP
Haass, C., Kaether, C., Thinakaran, G., & Sisodia, S. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006270 · Cited by 1,075 · see citing works
Self-citationAxonal transport deficits and neurodegenerative diseases
Millecamps, S., & Julien, J.-P. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3380 · Cited by 755 · 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
Amyloid Activates GSK-3β to Aggravate Neuronal Tauopathy in Bigenic Mice
Terwel, D., Muyllaert, D., Dewachter, I., Borghgraef, P., Croes, S., Devijver, H., & Van Leuven, F. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.070904 · Cited by 300 · see citing works
Tampellini, D., Magrané, J., Takahashi, R. H., Li, F., Lin, M. T., Almeida, C. G., & Gouras, G. K. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700373200 · Cited by 118 · see citing works
Axonal transport of APP and the spatial regulation of APP cleavage and function in neuronal cells
Brunholz, S., Sisodia, S., Lorenzo, A., Deyts, C., Kins, S., & Morfini, G. (2012) · Experimental Brain Research · doi:10.1007/s00221-011-2870-1 · Cited by 92 · see citing works
Reis, G. F., Yang, G., Szpankowski, L., Weaver, C., Shah, S. B., Robinson, J. T., Hays, T. S., Danuser, G., & Goldstein, L. S. B. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-11-0938 · Cited by 80 · see citing works
- Authors
- Goldsbury, C., Mocanu, M., Thies, E., Kaether, C., Haass, C., Keller, P., Biernat, J., Mandelkow, E., & Mandelkow, E.
- Affiliations
- Deutsches Elektronen-Synchrotron DESY (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Adolf-Butenandt-Institut für Physiologische Chemie, Physikalische Biochemie und Zellbiologie (DE)
- Meso Scale Discovery (United States) (US)
- Corresponding author
- Goldsbury, Claire
- Mandelkow, Eva‐Maria
- ORCID
- Venue
- Traffic
- Publisher
- Wiley
- Published
- 2006-05-31
- Volume
- 7
- Issue
- 7
- Pages
- 873-888
- ISSN
- 1398-9219 (ISSN-L)
- 1600-0854
- OpenAlex
- W1540823632
- Cited by
- 82
- References
- 56
- Citations by year
- 2024: 1 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 3 · 2015: 5 · 2014: 7 · 2013: 4 · 2012: 8
- FWCI
- 5.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Traffic (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- amyloid-beta production, APP trafficking, tau protein, BACE1, beta-secretase, vesicle trafficking, Alzheimer's disease, APP cleavage, microtubule-associated proteins
- MeSH terms
- Animals, Cells, Cultured, Chlorocebus aethiops, Cerebral Cortex, Gene Expression Regulation, Humans, Neurons, Peptide Fragments, Recombinant Proteins, Retinal Ganglion Cells, Amyloid beta-Peptides, tau Proteins, Rats, Wistar, Protein Transport, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
