The secreted APP ectodomain sAPPα, but not sAPPβ, protects neurons against Aβ oligomer-induced dendritic spine loss and increased tau phosphorylation
Open accessAbstract
AIM: The amyloid precursor protein (APP) is endoproteolytically processed to generate either the neurotoxic beta-amyloid peptide (Aβ) or the secreted ectodomain APP alpha (sAPPα). While neurotrophic properties of sAPPα were suggested in several studies, it is still unclear if and how sAPPα counteracts pathogenic effects of Aβ. Direct comparisons with sAPPβ, produced in the Aβ-generating pathway, are missing in order to determine the role of sAPPα's carbonyl-terminal end in its possible neuroprotective activity. METHODS: . The effects on tau phosphorylation and dendritic spine densities were assessed by western blot and confocal imaging, respectively. Co-administration of either sAPPα or sAPPβ was used to determine activity on Aβ-induced toxicity. RESULTS/DISCUSSION: We found that oligomeric Aβ strongly increased AT8 and AT180 phosphorylation of tau and caused a loss of dendritic spines. SAPPα completely abolished Aβ effects whereas sAPPβ had no such rescue activity. Interestingly, sAPPα or sAPPβ alone neither affected tau phosphorylation nor dendritic spine numbers. Together, our data suggest that sAPPα specifically protects neurons against Aβ-dependent toxicity supporting the strategy of activating α-secretase-dependent endoproteolytic APP processing to increase sAPPα shedding from the neuronal plasma membrane as a therapeutic intervention for the protection of dendritic spines and phospho-tau-dependent toxicity in Alzheimer's disease.
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?
sAPPα is protective against Aβ-induced toxicity.
“sAPPα plays an important role in neuronal plasticity/survival and has been shown to be protective against Aβ-induced toxicity [21].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [21]
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
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
Postina, R., Schroeder, A., Dewachter, I., Bohl, J., Schmitt, U., Kojro, E., Prinzen, C., Endres, K., Hiemke, C., Blessing, M., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20864 · Cited by 638 · see citing works
Wang, J., Xia, Y., Grundke, I., & Iqbal, K. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129031 · Cited by 532 · see citing works
Stein, T. D., Anders, N. J., DeCarli, C. S., Chan, S. L., Mattson, M. P., & Johnson, J. A. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2211-04.2004 · Cited by 276 · see citing works
Pathways by Which Aβ Facilitates Tau Pathology
Blurton-Jones, M. M., & LaFerla, F. M. (2006) · Current Alzheimer Research · doi:10.2174/156720506779025242 · Cited by 195 · see citing works
The Role of ADAM10 in Alzheimer’s Disease
Yuan, X., Sun, S., Tan, C., Yu, J., & Tan, L. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170061 · Cited by 160 · see citing works
Olsson, A., Höglund, K., Sjögren, M. J. C., Andreasen, N., Minthon, L., Lannfelt, L., Büerger, K., Möller, H., Hampel, H. J., Davidsson, P., et al. (2003) · Experimental Neurology · doi:10.1016/s0014-4886(03)00027-x · Cited by 132 · see citing works
Tackenberg, C., Grinschgl, S., Trutzel, A., Santuccione, A. C., Frey, M. C., Konietzko, U., Grimm, J., Brandt, R., & Nitsch, R. M. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.129 · Cited by 130 · see citing works
Self-citationTackenberg, C., & Brandt, R. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3590-09.2009 · Cited by 127 · see citing works
Self-citationThin, Stubby or Mushroom: Spine Pathology in Alzheimers Disease
Tackenberg, C., Ghori, A., & Brandt, R. (2009) · Current Alzheimer Research · doi:10.2174/156720509788486554 · Cited by 112 · see citing works
Self-citationCalcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss
Birnbaum, J. H., Bali, J., Rajendran, L., Nitsch, R. M., & Tackenberg, C. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.160 · Cited by 96 · see citing works
Self-citationHabib, A., Sawmiller, D. R., & Tan, J. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23823 · Cited by 95 · see citing works
Deng, J., Habib, A., Obregon, D. F., Barger, S. W., Giunta, B. N., Wang, Y., Hou, H., Sawmiller, D. R., & Tan, J. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13351 · Cited by 91 · see citing works
Cerebrospinal fluid biomarkers of β-amyloid metabolism in multiple sclerosis
Augutis, K., Axelsson, M., Portelius, E., Brinkmalm, G., Andreasson, U., Gustavsson, M. K., Malmeström, C., Lycke, J., Blennow, K., Zetterberg, H., et al. (2013) · Multiple Sclerosis Journal · doi:10.1177/1352458512460603 · Cited by 47 · see citing works
Thin, Stubby or Mushroom: Spine Pathology in Alzheimer's Disease
Tackenberg, C., Ghori, A., & Brandt, R. (2014) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9781608058525114020015 · Cited by 11 · see citing works
Self-citationγ-Secretase regulates the α-secretase cleavage of the Alzheimer’s disease, amyloid precursor protein
Siegenthaler, B. M., Bali, J., & Rajendran, L. (2016) · Matters · doi:10.19185/matters.201601000003 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
- Authors
- Tackenberg, C., & Nitsch, R. M.
- Affiliations
- University of Zurich (CH)
- Corresponding author
- Tackenberg, Christian
- Venue
- Molecular Brain
- Published
- 2019-03-29
- Volume
- 12
- Issue
- 1
- Pages
- 27-27
- ISSN
- 1756-6606 (ISSN-L)
- PMC
- PMC6440141
- OpenAlex
- W2942902227
- Cited by
- 56
- References
- 16
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 3 · 2023: 7 · 2022: 11 · 2021: 8 · 2020: 9 · 2019: 4
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Brain (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Deutsche Forschungsgemeinschaft (Ta762/1-1)
- 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, amyloid-beta oligomers, dendritic spine loss, tau phosphorylation, neuroprotection, alpha-secretase, APP processing, Alzheimer's disease, AT8
- MeSH terms
- Neuroprotection, Protein Domains, Humans, Peptide Fragments, Phosphorylation, Amyloid beta-Peptides, tau Proteins, Dendritic Spines
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
