CoChat
Sign Up
Cited by 210Alzheimer's disease research and treatmentsAxon Guidance and Neuronal SignalingNeurogenesis and neuroplasticity mechanisms

Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1

Open access
Young-Pearse, Tracy L, Chen, Allen C, Chang, Rui, Marquez, Cesar, Selkoe, Dennis J·2008·Neural Development
DOI 10.1186/1749-8104-3-15PMC PMC2442059
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: β-Amyloid precursor protein (APP) has been reported to play a role in the outgrowth of neurites from cultured neurons. Both cell-surface APP and its soluble, ectodomain cleavage product (APPs-α) have been implicated in regulating the length and branching of neurites in a variety of assays, but the mechanism by which APP performs this function is not understood. Results: Here, we report that APP is required for proper neurite outgrowth in a cell autonomous manner, both in vitro and in vivo . Neurons that lack APP undergo elongation of their longest neurite. Deletion of APLP1 or APLP2, homologues of APP, likewise stimulates neurite lengthening. Intriguingly, wild-type neurons exposed to APPs-α, the principal cleavage product of APP, also undergo neurite elongation. However, APPs-α is unable to stimulate neurite elongation in the absence of cellular APP expression. The outgrowth-enhancing effects of both APPs-α and the deletion of APP are inhibited by blocking antibodies to Integrin β1 (Itgβ1). Moreover, full length APP interacts biochemically with Itgβ1, and APPs-α can interfere with this binding. Conclusion: Our findings indicate that APPs-α regulates the function of APP in neurite outgrowth via the novel mechanism of competing with the binding of APP to Itgβ1.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/1749-8104-3-15

Cites

1 of 1 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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-integrin interaction is required for neurite outgrowth and contact guidance.

    “Accordingly, APP–integrin interaction is required for neurite outgrowth and contact guidance [123, 153].”

    From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [153]

    The Results show that APP interacts with integrin β1 and that blocking integrin β1 abolishes the neurite-outgrowth increase seen in APP-knockout or APPs-α-treated neurons. They do not establish that APP–integrin interaction is required for neurite outgrowth generally: the blocking antibody had no significant effect on neurite length in wild-type neurons. Our copy does not report a contact-guidance result (searched: contact guidance). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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

Flagged first, then by citations

Research works printed but not linked: 42

  1. Benowitz LI Rodriguez W Paskevich P Muson EJ Schenk D Neve RL The amyloid precursor protein is concentrated in neuronal lysosomes in normal and Alzheimer disease subjects Exp Neurol 1989 106 237 250 2591522 10.1016/0014-4886(89)90156-8 · DOI
  2. McGeer PL Akiyama H Kawamata T Yamada T Walker DG Ishii T Immunohistochemical localization of beta-amyloid precursor protein sequences in Alzheimer and normal brain tissue by light and electron microscopy J Neurosci Res 1992 31 428 442 1640495 10.1002/jnr.490310305 · DOI
  3. Jung SS Nalbantoglu J Cashman NR Alzheimer's beta-amyloid precursor protein is expressed on the surface of immediately ex vivo brain cells: a flow cytometric study J Neurosci Res 1996 46 336 348 8933373 10.1002/(SICI)1097-4547(19961101)46:3<336::AID-JNR7>3.0.CO;2-L · DOI
  4. Selkoe DJ Wolfe MS Presenilin: running with scissors in the membrane Cell 2007 131 215 221 17956719 10.1016/j.cell.2007.10.012 · DOI
  5. Esch FS Keim PS Beattie EC Blacher RW Culwell AR Oltersdorf T McClure D Ward PJ Cleavage of amyloid β-peptide during constitutive processing of its precursor Science 1990 248 1122 1124 2111583 10.1126/science.2111583 · DOI
  6. Selkoe DJ Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases Nat Cell Biol 2004 6 1054 1061 15516999 10.1038/ncb1104-1054 · DOI · Paper page
  7. Wasco W Bupp K Magendantz M Gusella J Tanzi RE Solomon F Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid β-protein precursor Proc Natl Acad Sci USA 1992 89 10758 10762 1279693 10.1073/pnas.89.22.10758 PMC50421 · DOI
  8. Wasco W Gurubhagavatula S Paradis MD Romano DM Sisodia SS Hyman BT Neve RL Tanzi RE Isolation and characterization of the human APLP2 gene encoding a homologue of the Alzheimer's associated amyloid β protein precursor Nature Genet 1993 5 95 99 8220435 10.1038/ng0993-95 · DOI
  9. Li Q Sudhof TC Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1 J Biol Chem 2004 279 10542 10550 14699153 10.1074/jbc.M310001200 · DOI
  10. Walsh DM Fadeeva JV LaVoie MJ Paliga K Eggert S Kimberly WT Wasco W Selkoe DJ gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins Biochemistry 2003 42 6664 6673 12779321 10.1021/bi027375c · DOI
  11. Scheinfeld MH Ghersi E Laky K Fowlkes BJ D'Adamio L Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription J Biol Chem 2002 277 44195 44201 12228233 10.1074/jbc.M208110200 · DOI
  12. Eggert S Paliga K Soba P Evin G Masters CL Weidemann A Beyreuther K The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation J Biol Chem 2004 279 18146 18156 14970212 10.1074/jbc.M311601200 · DOI
  13. Pastorino L Ikin AF Lamprianou S Vacaresse N Revelli JP Platt K Paganetti P Mathews PM Harroch S Buxbaum JD BACE (beta-secretase) modulates the processing of APLP2 in vivo Mol Cell Neurosci 2004 25 642 649 15080893 10.1016/j.mcn.2003.12.013 · DOI
  14. von Koch CS Zheng H Chen H Trumbauer M Thinakaran G Ploeg LH van der Price DL Sisodia SS Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice Neurobiol Aging 1997 18 661 669 9461064 10.1016/S0197-4580(97)00151-6 · DOI
  15. Zheng H Jiang M Trumbauer ME Sirinathsinghji DJS Hopkins R Smith DW Heavesn RP Dawson GR Boyce S Conner MW β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity Cell 1995 81 525 531 7758106 10.1016/0092-8674(95)90073-X · DOI
  16. Heber S Herms J Gajic V Hainfellner J Aguzzi A Rulicke T von Kretzschmar H von Koch C Sisodia S Tremml P Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members J Neurosci 2000 20 7951 7963 11050115 PMC6772747
  17. Perez RG Zheng H Ploeg LH Van der Koo EH The beta-amyloid precursor protein of Alzheimer's disease enhances neuron viability and modulates neuronal polarity J Neurosci 1997 17 9407 9414 9390996 PMC6573428
  18. Ring S Weyer SW Kilian SB Waldron E Pietrzik CU Filippov MA Herms J Buchholz C Eckman CB Korte M The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice J Neurosci 2007 27 7817 7826 17634375 10.1523/JNEUROSCI.1026-07.2007 PMC6672885 · DOI · Paper page
  19. Araki W Kitaguchi N Tokushima Y Ishii K Aratake H Shimohama S Nakamura S Kimura J Trophic effect of β-amyloid precursor ptotein on cerebral cortical neurons in culture Biochem Biophys Res Commun 1991 181 265 271 1958195 10.1016/S0006-291X(05)81412-3 · DOI
  20. Ohsawa I Hirose Y Ishiguro M Imai Y Ishiura S Kohsaka S Expression, purification, and neurotrophic activity of amyloid precursor protein-secreted forms produced by yeast Biochem Biophys Res Commun 1995 213 52 58 7639761 10.1006/bbrc.1995.2097 · DOI
  21. Milward EA Papadopoulos R Fuller SJ Moir RD Small D Beyreuther K Masters CL The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth Neuron 1992 9 129 137 1632967 10.1016/0896-6273(92)90228-6 · DOI
  22. Wallace WC Akar CA Lyons WE Amyloid precursor protein potentiates the neurotrophic activity of NGF Brain Res Mol Brain Res 1997 52 201 212 9495541 10.1016/S0169-328X(97)00258-1 · DOI
  23. Schmid RS Jo R Shelton S Kreidberg JA Anton ES Reelin, integrin and DAB1 interactions during embryonic cerebral cortical development Cereb Cortex 2005 15 1632 1636 15703255 10.1093/cercor/bhi041 · DOI
  24. Bamdad M Volle D Dastugue B Meiniel A Alpha1beta1-integrin is an essential signal for neurite outgrowth induced by thrombospondin type 1 repeats of SCO-spondin Cell Tissue Res 2004 315 15 25 14564503 10.1007/s00441-003-0793-2 · DOI
  25. Yamazaki T Koo EH Selkoe DJ Cell surface amyloid beta-protein precursor colocalizes with beta 1 integrins at substrate contact sites in neural cells J Neurosci 1997 17 1004 1010 8994055 PMC6573178
  26. Sabo SL Ikin AF Buxbaum JD Greengard P The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement J Cell Biol 2001 153 1403 1414 11425871 10.1083/jcb.153.7.1403 PMC2150733 · DOI · Paper page
  27. Storey E Beyreuther K Masters CL Alzheimer's disease amyloid precursor protein on the surface of cortical neurons in primary culture co-localizes with adhesion patch components Brain Res 1996 735 217 231 8911660 10.1016/0006-8993(96)00608-7 · DOI
  28. Rossjohn J Cappai R Feil SC Henry A McKinstry WJ Galatis D Hesse L Multhaup G Beyreuther K Masters CL Parker MW Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein Nat Struct Biol 1999 6 327 331 10201399 10.1038/7562 · DOI
  29. Loturco JJ Bai J The multipolar stage and disruptions in neuronal migration Trends Neurosci 2006 29 407 413 16713637 10.1016/j.tins.2006.05.006 · DOI
  30. Bai J Ramos RL Ackman JB Thomas AM Lee RV LoTurco JJ RNAi reveals doublecortin is required for radial migration in rat neocortex Nat Neurosci 2003 6 1277 1283 14625554 10.1038/nn1153 · DOI
  31. Clegg DO Novel roles for integrins in the nervous system Mol Cell Biol Res Commun 2000 3 1 7 10683310 10.1006/mcbr.1999.0175 · DOI
  32. Van Gassen G Annaert W Van Broeckhoven C Binding partners of Alzheimer's disease proteins: are they physiologically relevant? Neurobiol Dis 2000 7 135 151 10860781 10.1006/nbdi.2000.0306 · DOI
  33. Calderwood DA Fujioka Y de Pereda JM Garcia-Alvarez B Nakamoto T Margolis B McGlade CJ Liddington RC Ginsberg MH Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling Proc Natl Acad Sci USA 2003 100 2272 2277 12606711 10.1073/pnas.262791999 PMC151330 · DOI
  34. Burgess A Weng YQ Ypsilanti AR Cui X Caines G Aubert I Polysialic acid limits septal neurite outgrowth on laminin Brain Res 2007 1144 52 58 17335782 10.1016/j.brainres.2007.01.072 · DOI
  35. Muller U Bossy B Venstrom K Reichardt LF Integrin alpha 8 beta 1 promotes attachment, cell spreading, and neurite outgrowth on fibronectin Mol Biol Cell 1995 6 433 448 7626807 PMC301202
  36. Tarone G Hirsch E Brancaccio M De Acetis M Barberis L Balzac F Retta SF Botta C Altruda F Silengo L Integrin function and regulation in development Int J Dev Biol 2000 44 725 731 11061437
  37. Sabo SL Ikin AF Buxbaum JD Greengard P The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo J Neurosci 2003 23 5407 5415 12843239 PMC6741254
  38. Trommsdorff M Borg JP Margolis B Herz J Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein J Biol Chem 1998 273 33556 33560 9837937 10.1074/jbc.273.50.33556 · DOI
  39. Pietrzik CU Yoon IS Jaeger S Busse T Weggen S Koo EH FE65 constitutes the functional link between the low-density lipoprotein receptor-related protein and the amyloid precursor protein J Neurosci 2004 24 4259 4265 15115822 10.1523/JNEUROSCI.5451-03.2004 PMC6729272 · DOI
  40. Ikin AF Sabo SL Lanier LM Buxbaum JD A macromolecular complex involving the amyloid precursor protein (APP) and the cytosolic adapter FE65 is a negative regulator of axon branching Mol Cell Neurosci 2007 35 57 63 17383198 10.1016/j.mcn.2007.02.003 PMC3622246 · DOI · Paper page
  41. Hoe H-S Lee KJ Lee J Markova AJ Lee Y Pak DT Hyman B Bu G Rebeck GW Reelin-APP interaction promotes neurite outgrowth in hippocampal neurons Society for Neuroscience 37th Annual Conference; San Diego, CA 2007 331 313
  42. Hemming ML Selkoe DJ Farris W Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease Neurobiol Dis 2007 26 273 281 17321748 10.1016/j.nbd.2007.01.004 PMC2377010 · DOI

Cited by

Sorted by citations

Authors
Young-Pearse, T. L., Chen, A. C., Chang, R., Marquez, C., & Selkoe, D. J.
Affiliations
Brigham and Women's Hospital (US)
Corresponding author
Selkoe, Dennis J
ORCID
Venue
Neural Development
Publisher
Springer Science and Business Media LLC
Published
2008-06-23
Volume
3
Issue
1
Pages
15-15
ISSN
1749-8104 (ISSN-L)
DOI
10.1186/1749-8104-3-15
PMC
PMC2442059
OpenAlex
W2170670144
Cited by
210
References
1
Citations by year
2026: 14 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 11 · 2019: 10 · 2018: 11 · 2017: 15 · 2016: 17 · 2015: 13 · 2014: 13 · 2013: 15 · 2012: 20
FWCI
8.09
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Neural Development (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institutes of Health (1f32ns053320-01a1)
  • National Institute on Aging (R0I AG06173, R01AG006173)
  • National Institute of Neurological Disorders and Stroke (F32 NS053320-01A1, F32 NS053320)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
amyloid precursor protein, neurite outgrowth, beta1 integrin, APLP1, APLP2, neurite elongation
MeSH terms
Animals, Cells, Cultured, Cerebral Cortex, Cricetulus, Female, Cricetinae, Hippocampus, Humans, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Pregnancy, Transfection, CHO Cells, Neurites, Amyloid beta-Protein Precursor, Rats, Sprague-Dawley, Mice, Knockout, Integrin beta1, Green Fluorescent Proteins, Mice, 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