CoChat
Sign Up
Cited by 242Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Presynaptic and Postsynaptic Interaction of the Amyloid Precursor Protein Promotes Peripheral and Central Synaptogenesis

Open access
Wang, Zilai, Wang, Baiping, Yang, Li, Guo, Qinxi, Aithmitti, Nadia, Songyang, Zhou, Zheng, Hui·2009·The Journal of Neuroscience
DOI 10.1523/jneurosci.2132-09.2009PMC PMC2757256
Open this paper in CoChat — free accountOpen PDF

Abstract

A critical role of the amyloid precursor protein (APP) in Alzheimer's disease (AD) pathogenesis has been well established. However, the physiological function of APP remains elusive and much debated. We reported previously that the APP family of proteins is essential in mediating the developing neuromuscular synapse. In the current study, we created a conditional allele of APP and deleted APP in presynaptic motor neuron or postsynaptic muscle. Crossing these alleles onto the APP-like protein 2 -null background reveals that, unexpectedly, inactivating APP in either compartment results in neuromuscular synapse defects similar to the germline deletion and that postsynaptic APP is obligatory for presynaptic targeting of the high-affinity choline transporter and synaptic transmission. Using a HEK293 and primary hippocampus mixed-culture assay, we report that expression of APP in HEK293 cells potently promotes synaptogenesis in contacting axons. This activity is dependent on neuronal APP and requires both the extracellular and intracellular domains; the latter forms a complex with Mint1 and Cask and is replaceable by the corresponding SynCAM (synaptic cell adhesion molecule) sequences. These in vitro and in vivo studies identify APP as a novel synaptic adhesion molecule. We postulate that transsynaptic APP interaction modulates its synaptic function and that perturbed APP synaptic adhesion activity may contribute to synaptic dysfunction and AD pathogenesis.

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 · 10.1523/jneurosci.2132-09.2009

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?

  • After differentiation, APP acts as a synaptic adhesion molecule required at both presynaptic and postsynaptic membranes for correct synapse patterning.

    “After differentiation, APP acts as a synaptic adhesion molecule required at both presynaptic and postsynaptic membranes for correct synapse patterning [142].”

    From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [142]

    The Abstract and Discussion identify APP as a synaptic adhesion molecule, and the Results section on neuromuscular synapse patterning reports that APP from both presynaptic neurons and postsynaptic muscle is required for normal patterning. The paper studies developing synapses; it does not establish the claim’s timing of “after differentiation.” No page numbers are available in our copy. (LLM, conf=0.82)

    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: 48

  1. Akaaboune M Allinquant B Farza H Roy K Magoul R Fiszman M Festoff BW Hantai D 2000 Developmental regulation of amyloid precursor protein at the neuromuscular junction in mouse skeletal muscle Mol Cell Neurosci 15 355 367 10845772
  2. Akins MR Biederer T 2006 Cell-cell interactions in synaptogenesis Curr Opin Neurobiol 16 83 89 16427268
  3. Ashley J Packard M Ataman B Budnik V 2005 Fasciclin II signals new synapse formation through amyloid precursor protein and the scaffolding protein dX11/Mint J Neurosci 25 5943 5955 15976083 PMC6724788
  4. Autism Genome Project C 2007 Mapping autism risk loci using genetic linkage and chromosomal rearrangements Nat Genet 39 319 328 17322880 PMC4867008
  5. Biederer T Sudhof TC 2000 Mints as adaptors. Direct binding to neurexins and recruitment of munc18 J Biol Chem 275 39803 39806 11036064
  6. Biederer T Scheiffele P 2007 Mixed-culture assays for analyzing neuronal synapse formation Nat Protoc 2 670 676 17406629
  7. Biederer T Sara Y Mozhayeva M Atasoy D Liu X Kavalali ET Sudhof TC 2002 SynCAM, a synaptic adhesion molecule that drives synapse assembly Science 297 1525 1531 12202822
  8. Chang EH Savage MJ Flood DG Thomas JM Levy RB Mahadomrongkul V Shirao T Aoki C Huerta PT 2006 AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice Proc Natl Acad Sci U S A 103 3410 3415 16492745 PMC1413872
  9. Chen LY Liu D Songyang Z 2007 Telomere maintenance through spatial control of telomeric proteins Mol Cell Biol 27 5898 5909 17562870 PMC1952115
  10. Dalva MB McClelland AC Kayser MS 2007 Cell adhesion molecules: signalling functions at the synapse Nat Rev Neurosci 8 206 220 17299456 PMC4756920
  11. Fogel AI Akins MR Krupp AJ Stagi M Stein V Biederer T 2007 SynCAMs organize synapses through heterophilic adhesion J Neurosci 27 12516 12530 18003830 PMC6673342
  12. Fox MA Umemori H 2006 Seeking long-term relationship: axon and target communicate to organize synaptic differentiation J Neurochem 97 1215 1231 16638017
  13. Graf ER Zhang X Jin SX Linhoff MW Craig AM 2004 Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins Cell 119 1013 1026 15620359 PMC2826211
  14. Gralle M Oliveira CL Guerreiro LH McKinstry WJ Galatis D Masters CL Cappai R Parker MW Ramos CH Torriani I Ferreira ST 2006 Solution conformation and heparin-induced dimerization of the full-length extracellular domain of the human amyloid precursor protein J Mol Biol 357 493 508 16436282
  15. Hata Y Butz S Sudhof TC 1996 CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins J Neurosci 16 2488 2494 8786425 PMC6578772
  16. Hoe HS Fu Z Makarova A Lee JY Lu C Feng L Pajoohesh-Ganji A Matsuoka Y Hyman BT Ehlers MD 2009 The effects of amyloid precursor protein on post-synaptic composition and activity J Biol Chem 284 8495 8506 19164281 PMC2659208
  17. Hornsten A Lieberthal J Fadia S Malins R Ha L Xu X Daigle I Markowitz M O'Connor G Plasterk R Li C 2007 APL-1, a Caenorhabditis elegans protein related to the human beta-amyloid precursor protein, is essential for viability Proc Natl Acad Sci U S A 104 1971 1976 17267616 PMC1794273
  18. Hsieh H Boehm J Sato C Iwatsubo T Tomita T Sisodia S Malinow R 2006 AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss Neuron 52 831 843 17145504 PMC1850952
  19. Jamain S Quach H Betancur C Rastam M Colineaux C Gillberg IC Soderstrom H Giros B Leboyer M Gillberg C Bourgeron T Paris Autism Research International Sibpair S 2003 Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism Nat Genet 34 27 29 12669065 PMC1925054
  20. Kaden D Munter LM Joshi M Treiber C Weise C Bethge T Voigt P Schaefer M Beyermann M Reif B Multhaup G 2008 Homophilic interactions of the amyloid precursor protein (APP) ectodomain are regulated by the loop region and affect beta-secretase cleavage of APP J Biol Chem 283 7271 7279 18182389
  21. Kamenetz F Tomita T Hsieh H Seabrook G Borchelt D Iwatsubo T Sisodia S Malinow R 2003 APP processing and synaptic function Neuron 37 925 937 12670422
  22. Kerppola TK 2006 Design and implementation of bimolecular fluorescence complementation (BiFC) assays for the visualization of protein interactions in living cells Nat protoc 1 1278 1286 17406412 PMC2518326
  23. Kummer TT Misgeld T Sanes JR 2006 Assembly of the postsynaptic membrane at the neuromuscular junction: paradigm lost Curr Opin Neurobiol 16 74 82 16386415
  24. Lan ZJ Xu X Cooney AJ 2004 Differential oocyte-specific expression of Cre recombinase activity in GDF-9-iCre, Zp3cre, and Msx2Cre transgenic mice Biol Reprod 71 1469 1474 15215191
  25. Lazarov O Lee M Peterson DA Sisodia SS 2002 Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice J Neurosci 22 9785 9793 12427834 PMC6757836
  26. Ma QH Futagawa T Yang WL Jiang XD Zeng L Takeda Y Xu RX Bagnard D Schachner M Furley AJ Karagogeos D Watanabe K Dawe GS Xiao ZC 2008 A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis Nat Cell Biol 10 283 294 18278038
  27. Moscoso LM Cremer H Sanes JR 1998 Organization and reorganization of neuromuscular junctions in mice lacking neural cell adhesion molecule, tenascin-C, or fibroblast growth factor-5 J Neurosci 18 1465 1477 9454855 PMC6792746
  28. Muresan V Varvel NH Lamb BT Muresan Z 2009 The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites J Neurosci 29 3565 3578 19295161 PMC2669751
  29. Muresan Z Muresan V 2005 c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein J Neurosci 25 3741 3751 15829626 PMC6724916
  30. Nikolaev A McLaughlin T O'Leary DDM Tessier-Lavigne M 2009 APP binds DR6 to trigger axon pruning and neuron death via distinct caspases Nature 457 981 990 19225519 PMC2677572
  31. Osterfield M Egelund R Young LM Flanagan JG 2008 Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system Development 135 1189 1199 18272596
  32. Papaioannou VE Boehringer R 2005 Mouse phenotypes: a handbook of mutation analysis Cold Spring Harbor Laboratory Press
  33. Patton BL Miner JH Chiu AY Sanes JR 1997 Distribution and function of laminins in the neuromuscular system of developing, adult, and mutant mice J Cell Biol 139 1507 1521 9396756 PMC2132624
  34. Ring S Weyer SW Kilian SB Waldron E Pietrzik CU Filippov MA Herms J Buchholz C Eckman CB Korte M Wolfer DP Muller UC 2007 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 27 7817 7826 17634375 PMC6672885
  35. Sara Y Biederer T Atasoy D Chubykin A Mozhayeva MG Sudhof TC Kavalali ET 2005 Selective capability of SynCAM and neuroligin for functional synapse assembly J Neurosci 25 260 270 15634790 PMC6725191
  36. Scheiffele P Fan J Choih J Fetter R Serafini T 2000 Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons Cell 101 657 669 10892652
  37. Schwander M Shirasaki R Pfaff SL Muller U 2004 Beta1 integrins in muscle, but not in motor neurons, are required for skeletal muscle innervation J Neurosci 24 8181 8191 15371519 PMC6729792
  38. Selkoe DJ 2002 Alzheimer's disease is a synaptic failure Science 298 789 791 12399581
  39. Soba P Eggert S Wagner K Zentgraf H Siehl K Kreger S Lower A Langer A Merdes G Paro R Masters CL Muller U Kins S Beyreuther K 2005 Homo- and heterodimerization of APP family members promotes intercellular adhesion EMBO J 24 3624 3634 16193067 PMC1276707
  40. Tang W Ingalls CP Durham WJ Snider J Reid MB Wu G Matzuk MM Hamilton SL 2004 Altered excitation-contraction coupling with skeletal muscle specific FKBP12 deficiency FASEB J 18 1597 1599 15289441
  41. Tronche F Kellendonk C Kretz O Gass P Anlag K Orban PC Bock R Klein R Schutz G 1999 Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety Nat Genet 23 99 103 10471508
  42. von Koch CS Zheng H Chen H Trumbauer M Thinakaran G van der Ploeg LH Price DL Sisodia SS 1997 Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice Neurobiol Aging 18 661 669 9461064
  43. Wang B Yang L Wang Z Zheng H 2007 Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter Proc Natl Acad Sci U S A 104 14140 14145 17709753 PMC1955810
  44. Wang P Yang G Mosier DR Chang P Zaidi T Gong YD Zhao NM Dominguez B Lee KF Gan WB Zheng H 2005 Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2 J Neurosci 25 1219 1225 15689559 PMC6725967
  45. Wang Y Ha Y 2004 The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain Mol Cell 15 343 353 15304215
  46. Xu W Schluter OM Steiner P Czervionke BL Sabatini B Malenka RC 2008 Molecular dissociation of the role of PSD-95 in regulating synaptic strength and LTD Neuron 57 248 262 18215622 PMC3147180
  47. Zhang Z Lee CH Mandiyan V Borg JP Margolis B Schlessinger J Kuriyan J 1997 Sequence-specific recognition of the internalization motif of the Alzheimer's amyloid precursor protein by the X11 PTB domain EMBO Journal 16 6141 6150 9321393 PMC1326298
  48. Zheng H Koo EH 2006 The amyloid precursor protein: beyond amyloid Mol Neurodegener 1 5 16930452 PMC1538601

Cited by

Sorted by citations

Authors
Wang, Z., Wang, B., Yang, L., Guo, Q., Aithmitti, N., Songyang, Z., & Zheng, H.
Affiliations
Baylor College of Medicine (US)
Corresponding author
Zheng, Hui
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2009-09-02
Volume
29
Issue
35
Pages
10788-10801
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.2132-09.2009
PMC
PMC2757256
OpenAlex
W2048558199
Cited by
242
References
1
Citations by year
2026: 5 · 2025: 9 · 2024: 7 · 2023: 15 · 2022: 8 · 2021: 8 · 2020: 11 · 2019: 14 · 2018: 11 · 2017: 26 · 2016: 22 · 2015: 17 · 2014: 18 · 2013: 19 · 2012: 12
FWCI
10.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • National Institutes of Health
  • School of Medicine, Stanford University
  • Intellectual and Developmental Disabilities Research Center (HD024064)
  • National Institute on Aging (AG032051, AG033467, R01AG032051, R01AG033467)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 024064, P30HD024064)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid precursor protein, synaptogenesis, neuromuscular synapse, choline transporter, synaptic transmission, synaptic adhesion molecules, Mint1, CASK, Alzheimer's disease, motor neurons, muscle, hippocampus, conditional alleles
MeSH terms
Animals, Cell Communication, Cell Line, Cells, Cultured, Central Nervous System, Female, Humans, Mice, Inbred C57BL, Mice, Transgenic, Synaptic Transmission, Pregnancy, Synapses, Amyloid beta-Protein Precursor, Presynaptic Terminals, Peripheral Nervous System, Mice, Knockout, Coculture Techniques, Mice, Synaptic Potentials, Neurogenesis

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