CoChat
Sign Up
Cited by 44Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Knockdown of Amyloid Precursor Protein: Biological Consequences and Clinical Opportunities

Open access
Gabriele, Rebecca M. C., Abel, Emily, Fox, Nick C., Wray, Selina, Arber, Charles·2022·Frontiers in Neuroscience
DOI 10.3389/fnins.2022.835645PMC PMC8964081
Open this paper in CoChat — free accountOpen PDF

Abstract

Amyloid precursor protein ( APP ) and its cleavage fragment Amyloid-β (Aβ) have fundamental roles in Alzheimer’s disease (AD). Genetic alterations that either increase the overall dosage of APP or alter its processing to favour the generation of longer, more aggregation prone Aβ species, are directly causative of the disease. People living with one copy of APP are asymptomatic and reducing APP has been shown to lower the relative production of aggregation-prone Aβ species in vitro . For these reasons, reducing APP expression is an attractive approach for AD treatment and prevention. In this review, we will describe the structure and the known functions of APP and go on to discuss the biological consequences of APP knockdown and knockout in model systems. We highlight progress in therapeutic strategies to reverse AD pathology via reducing APP expression. We conclude that new technologies that reduce the dosage of APP expression may allow disease modification and slow clinical progression, delaying or even preventing onset.

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 · 10.3389/fnins.2022.835645

Cites

13 of 13 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?

  • In trisomy 21 (Down syndrome), the additional copy of chromosome 21 leads to APP gene overexpression, causing excessive Aβ accumulation and near-universal development of amyloid plaques and Alzheimer-type dementia by the fifth decade of life.

    “Interestingly, in trisomy 21 (Down syndrome), the additional copy of chromosome 21 leads to APP gene overexpression, causing excessive Aβ accumulation and near-universal development of amyloid plaques and Alzheimer-type dementia by the fifth decade of life [150, 151].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [150]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    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: 115

  1. Akimov V. Barrio-Hernandez I. Hansen S. V. F. Hallenborg P. Pedersen A. K. Bekker-Jensen D. B. (2018). Ubisite approach for comprehensive mapping of lysine and n-terminal ubiquitination sites. Nat. Struct. Mol. Biol. 25: 84. 10.1038/s41594-018-0084-y 29967540 · DOI
  2. Allinson T. M. J. Parkin E. T. Turner A. J. Hooper N. M. (2003). ADAMs family members as amyloid precursor protein α-secretases. J. Neurosci. Res. 74 342– 352. 10.1002/jnr.10737 14598310 · DOI
  3. Andrew R. J. Kellett K. A. B. Thinakaran G. Hooper N. M. (2016). A greek tragedy: the growing complexity of Alzheimer amyloid precursor protein proteolysis. J. Biol. Chem. 291 19235– 19244. 10.1074/jbc.R116.746032 27474742 PMC5016663 · DOI
  4. Arber C. Lovejoy C. Harris L. Willumsen N. Alatza A. Casey J. M. (2021). Familial Alzheimer’s disease mutations in PSEN1 lead to premature human stem cell neurogenesis. Cell Rep. 34: 108615. 10.1016/j.celrep.2020.108615 33440141 PMC7809623 · DOI · Paper page
  5. Banati R. B. Gehrmann J. Czech C. Mönning U. Jones L. L. König G. (1993). Early and rapid de novo synthesis of alzheimer βA4-Amyloid precursor protein (APP) in activated microglia. Glia 9 199– 210. 10.1002/glia.440090305 7507467 · DOI
  6. Bergström P. Agholme L. Nazir F. H. Satir T. M. Toombs J. Wellington H. (2016). Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation. Sci. Rep. 6: 200. 10.1038/srep29200 27383650 PMC4935877 · DOI
  7. Bhattacharyya R. Black S. E. Lotlikar M. S. Fenn R. H. Jorfi M. Kovacs D. M. (2021). Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes. Cell Rep. 35: 109134. 10.1016/j.celrep.2021.109134 34010653 PMC8287518 · DOI
  8. Boix C. P. Lopez-Font I. Cuchillo-Ibañez I. Sáez-Valero J. (2020). Amyloid precursor protein glycosylation is altered in the brain of patients with Alzheimer’s disease. Alzheimer’s Res. Ther. 12 1– 15. 10.1186/s13195-020-00664-9 32787955 PMC7425076 · DOI
  9. Borg J. P. Ooi J. Levy E. Margolis B. (1996). The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. Mol. Cell. Biol. 16 6229– 6241. 10.1128/MCB.16.11.6229 8887653 PMC231626 · DOI · Paper page
  10. Bukhari H. Glotzbach A. Kolbe K. Leonhardt G. Loosse C. Müller T. (2017). Small things matter: implications of APP intracellular domain AICD nuclear signaling in the progression and pathogenesis of Alzheimer’s disease. Prog. Neurobiol. 156 189– 213. 10.1016/j.pneurobio.2017.05.005 28587768 · DOI
  11. Caillé I. Allinquant B. Dupont E. Bouillot C. Langer A. Müller U. (2004). Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone. Development (Cambridge, England) 131 2173– 2181. 10.1242/dev.01103 15073156 · DOI
  12. Caldwell J. H. Klevanski M. Saar M. Müller U. C. (2013). Roles of the amyloid precursor protein family in the peripheral nervous system. Mech. Dev. 130 433– 446. 10.1016/j.mod.2012.11.001 23201910 · DOI
  13. Cao X. (2001). A transcriptively active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293 115– 120. 10.1126/science.1058783 11441186 · DOI · Paper page
  14. Chang J. L. Hinrich A. J. Roman B. Norrbom M. Rigo F. Marr R. A. (2018). Targeting amyloid-β precursor protein, APP, splicing with antisense oligonucleotides reduces toxic amyloid-β production. Mol. Ther. 26 1539– 1551. 10.1016/j.ymthe.2018.02.029 29628304 PMC5986716 · DOI
  15. Chauhan N. B. Siegel G. J. (2007). Antisense inhibition at the β-secretase-site of β-amyloid precursor protein reduces cerebral amyloid and acetyl cholinesterase activity in Tg2576. Neuroscience 146 143– 151. 10.1016/j.neuroscience.2007.01.008 17303345 PMC1955231 · DOI
  16. Chávez-Gutiérrez L. Bammens L. Benilova I. Vandersteen A. Benurwar M. Borgers M. (2012). The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 31 2261– 2274. 10.1038/emboj.2012.79 22505025 PMC3364747 · DOI · Paper page
  17. Chen G. Xu T. Yan Y. Zhou Y. Jiang Y. Melcher K. (2017). Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin. 38 1205– 1235. 10.1038/aps.2017.28 28713158 PMC5589967 · DOI · Paper page
  18. Coric V. van Dyck C. H. Salloway S. Andreasen N. Brody M. Richter R. W. (2012). Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol. 69 1430– 1440. 10.1001/archneurol.2012.2194 22892585 · DOI
  19. Corrigan F. Thornton E. Roisman L. C. Leonard A. V. Vink R. Blumbergs P. C. (2014). The neuroprotective activity of the amyloid precursor protein against traumatic brain injury is mediated via the heparin binding site in residues 96-110. J. Neurochem. 128 196– 204. 10.1111/jnc.12391 23919582 · DOI
  20. Crooke S. T. Baker B. F. Crooke R. M. Liang X. (2021a). Antisense technology: an overview and prospectus. Nat. Rev. Drug Dis. 20 427– 453. 10.1038/s41573-021-00162-z 33762737 · DOI · Paper page
  21. Crooke S. T. Liang X. H. Baker B. F. Crooke R. M. (2021b). Antisense technology: a review. J. Biol. Chem. 296: 416. 10.1016/j.jbc.2021.100416 33600796 PMC8005817 · DOI
  22. Daoutsali E. Hailu T. T. Buijsen R. A. M. Pepers B. A. van der Graaf L. M. Verbeek M. M. (2021). Antisense oligonucleotide-induced amyloid precursor protein splicing modulation as a therapeutic approach for dutch-type cerebral amyloid angiopathy. Nucleic Acid Ther. 31 351– 363. 10.1089/nat.2021.0005 34061681 PMC8823675 · DOI
  23. Dawson G. R. Seabrook G. R. Zheng H. Smith D. W. Graham S. O’Dowd G. (1999). Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the β-amyloid precursor protein. Neuroscience 90 1– 13. 10.1016/S0306-4522(98)00410-2 10188929 · DOI
  24. de Giorgio L. A. Shimizu Y. Chun H. S. Cho B. P. Sugama S. Joh T. H. (2002). APP knockout attenuates microglial activation and enhances neuron survival in substantia nigra compacta after axotomy. GLIA 38 174– 178. 10.1002/glia.10052 11948811 · DOI
  25. Decock M. Haylani L. Stanga S. Dewachter I. Octave J.-N. Smith S. O. (2015). Analysis by a highly sensitive split luciferase assay of the regions involved in APP dimerization and its impact on processing. FEBS Open. Bio. 5 763– 773. 10.1016/j.fob.2015.09.002 26500837 PMC4588712 · DOI
  26. Deyts C. Clutter M. Herrera S. Jovanovic N. Goddi A. Parent A. T. (2016). Loss of presenilin function is associated with a selective gain of APP function. eLife 5: e15645. 10.7554/eLife.15645 27196744 PMC4915812 · DOI
  27. Doody R. S. Raman R. Farlow M. Iwatsubo T. Vellas B. Joffe S. (2013). A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. New Eng. J. Med. 369 341– 350. 10.1056/NEJMoa1210951 23883379 · DOI · Paper page
  28. Eimer W. A. Vijaya Kumar D. K. Navalpur Shanmugam N. K. Rodriguez A. S. Mitchell T. Washicosky K. J. (2018). Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 99 56– 63e3. 10.1016/j.neuron.2018.06.030 30001512 PMC6075814 · DOI · Paper page
  29. Fanutza T. del Prete D. Ford M. J. Castillo P. E. D’Adamio L. (2015). APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses. eLife 4: e09743. 10.7554/eLife.09743 26551565 PMC4755753 · DOI
  30. Farr S. A. Erickson M. A. Niehoff M. L. Banks W. A. Morley J. E. (2014). Central and peripheral administration of antisense oligonucleotide targeting amyloid-β protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576 (AβPPswe) mice. J. Alzheimer’s Dis. 40 1005– 1016. 10.3233/JAD-131883 24577464 PMC4136536 · DOI
  31. Fitzjohn S. M. Morton R. A. Kuenzi F. Davies C. H. Seabrook G. R. Collingridge G. L. (2000). Similar levels of long-term potentiation in amyloid precursor protein -null and wild-type mice in the CA1 region of picrotoxin treated slices. Neurosci. Lett. 288 9– 12. 10.1016/s0304-3940(00)01204-0 10869803 · DOI
  32. Furukawa K. Sopher B. L. Rydel R. E. Begley J. G. Pham D. G. Martin G. M. (1996). Increased activity-regulating and neuroprotective efficacy of α- secretase-derived secreted amyloid precursor protein conferred by a C- terminal heparin-binding domain. J. Neurochem. 67 1882– 1896. 10.1046/j.1471-4159.1996.67051882.x 8863493 · DOI
  33. George A. A. Vieira J. M. Xavier-Jackson C. Gee M. T. Cirrito J. R. Bimonte-Nelson H. A. (2021). Implications of oligomeric amyloid-beta (oAβ42) signaling through α7β2-nicotinic acetylcholine receptors (nAChRs) on basal forebrain cholinergic neuronal intrinsic excitability and cognitive decline. J. Neurosci. 41 555– 575. 10.1523/JNEUROSCI.0876-20.2020 33239400 PMC7821864 · DOI
  34. Goate A. Chartier-Harlin M.-C. Mullan M. Brown J. Crawford F. Fidani L. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349 704– 706. 10.1038/349704a0 1671712 · DOI · Paper page
  35. Gralle M. Oliveira C. L. P. Guerreiro L. H. McKinstry W. J. Galatis D. Masters C. L. (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. 10.1016/j.jmb.2005.12.053 16436282 · DOI
  36. Grangeon L. Cassinari K. Rousseau S. Croisile B. Formaglio M. Moreaud O. (2021). Early-onset cerebral amyloid angiopathy and alzheimer disease related to an APP locus triplication. Neurol. Genet. 7: e609. 10.1212/nxg.0000000000000609 34532568 PMC8439959 · DOI
  37. Gunawardena S. Goldstein L. S. B. (2001). Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32 389– 401. 10.1016/s0896-6273(01)00496-2 11709151 · DOI · Paper page
  38. György B. Lööv C. Zaborowski M. P. Takeda S. Kleinstiver B. P. Commins C. (2018). CRISPR/Cas9 mediated disruption of the swedish APP allele as a therapeutic approach for early-onset Alzheimer’s disease. Mol. Ther. Nucleic Acids 11 429– 440. 10.1016/j.omtn.2018.03.007 29858078 PMC5992788 · DOI
  39. Haapasalo A. Kovacs D. M. (2011). The many substrates of presenilin/γ-secretase. J. Alzheimer’s Dis. 25 3– 28. 10.3233/JAD-2011-101065 21335653 PMC3281584 · DOI
  40. Haass C. Hung A. Selkoe D. (1991). Processing of beta-amyloid precursor protein in microglia and astrocytes favors an internal localization over constitutive secretion. J. Neurosci. 11 3783– 3793. 10.1523/JNEUROSCI.11-12-03783.1991 1744690 PMC6575298 · DOI
  41. Heber S. Herms J. Gajic V. Hainfellner J. Aguzzi A. Rulicke T. (2000). Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J. Neurosci. 20 7951– 7963. 10.1523/jneurosci.20-21-07951.2000 11050115 PMC6772747 · DOI
  42. Hendrickx A. Pierrot N. Tasiaux B. Schakman O. Brion J.-P. Kienlen-Campard P. (2013). Epigenetic induction of EGR-1 expression by the amyloid precursor protein during exposure to novelty. PLoS One 8: e74305– e74305. 10.1371/journal.pone.0074305 24066134 PMC3774615 · DOI
  43. Hendrickx A. Pierrot N. Tasiaux B. Schakman O. Kienlen-Campard P. de Smet C. (2014). Epigenetic regulations of immediate early genes expression involved in memory formation by the amyloid precursor protein of Alzheimer disease. PLoS One 9: e99467– e99467. 10.1371/journal.pone.0099467 24919190 PMC4053420 · DOI
  44. Hick M. Herrmann U. Weyer S. W. Mallm J.-P. Tschäpe J.-A. Borgers M. (2015). Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity. Acta Neuropathol. 129 21– 37. 10.1007/s00401-014-1368-x 25432317 · DOI
  45. Hornsten A. Lieberthal J. Fadia S. Malins R. Ha L. Xu X. (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. 10.1073/pnas.0603997104 17267616 PMC1794273 · DOI
  46. Hsiao K. Chapman P. Nilsen S. Eckman C. Harigaya Y. Younkin S. (1996). Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274 99– 102. 10.1126/science.274.5284.99 8810256 · DOI · Paper page
  47. Hu N. W. Corbett G. T. Moore S. Klyubin I. O’Malley T. T. Walsh D. M. (2018). Extracellular forms of Aβ and tau from iPSC models of Alzheimer’s disease disrupt synaptic plasticity. Cell Rep. 23 1932– 1938. 10.1016/j.celrep.2018.04.040 29768194 PMC5972225 · DOI
  48. Hung C. O. Y. Livesey F. J. (2018). Altered γ-secretase processing of APP disrupts lysosome and autophagosome function in monogenic Alzheimer’s disease. Cell Rep. 25 3647– 3660.e2. 10.1016/j.celrep.2018.11.095 30590039 PMC6315085 · DOI · Paper page
  49. Hunter S. Brayne C. (2018). Understanding the roles of mutations in the amyloid precursor protein in alzheimer disease. Mol. Psychiatry 23 81– 93. 10.1038/mp.2017.218 29112196 · DOI · Paper page
  50. Jin L. W. Ninomiya H. Roch J. M. Schubert D. Masliah E. Otero D. A. C. (1994). Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J. Neurosci. 14 5461– 5470. 10.1523/jneurosci.14-09-05461.1994 8083748 PMC6577069 · DOI
  51. Kang J. Lemaire H. G. Unterbeck A. Salbaum J. M. Masters C. L. Grzeschik K. H. (1987). The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325 733– 736. 10.1038/325733a0 2881207 · DOI · Paper page
  52. Klein S. Goldman A. Lee H. Ghahremani S. Bhakta V. Nelson S. F. (2016). Truncating mutations in APP cause a distinct neurological phenotype. Ann. Neurol. 80 456– 460. 10.1002/ana.24727 27422356 PMC7034636 · DOI
  53. Kreis A. Desloovere J. Suelves N. Pierrot N. Yerna X. Issa F. (2021). Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission. Sci. Rep. 11: 17600. 10.1038/s41598-021-97144-3 34475508 PMC8413381 · DOI
  54. Kumar V. B. Farr S. A. Flood J. F. Kamlesh V. Franko M. Banks W. A. (2000). Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice. Peptides 21 1769– 1775. 10.1016/S0196-9781(00)00339-9 11150636 · DOI
  55. Kwart D. Gregg A. Scheckel C. Murphy E. A. Paquet D. Duffield M. (2019). A large panel of isogenic APP and PSEN1 mutant human iPSC neurons reveals shared endosomal abnormalities mediated by APP β-CTFs, Not Aβ. Neuron 104 256– 270.e5. 10.1016/j.neuron.2019.07.010 31416668 · DOI
  56. Lasala M. Fabiani C. Corradi J. Antollini S. Bouzat C. (2019). Molecular modulation of human α7 nicotinic receptor by amyloid-β peptides. Front. Cell. Neurosci. 13: 1– 11. 10.3389/fncel.2019.00037 30800059 PMC6376857 · DOI
  57. LeBlanc A. C. Chen H. Y. Autilio-Gambetti L. Gambetti P. (1991). Differential APP gene expression in rat cerebral cortex, meninges, and primary astroglial, microglial and neuronal cultures. FEBS Lett. 292 171– 178. 10.1016/0014-5793(91)80861-V 1959603 · DOI
  58. Li H. Wang B. Wang Z. Guo Q. Tabuchi K. Hammer R. E. (2010). Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP. Proc. Natl. Acad. Sci. U.S.A. 107 17362– 17367. 10.1073/pnas.1012568107 20855613 PMC2951422 · DOI
  59. Li H. L. Roch J. M. Sundsmo M. Otero D. Sisodia S. Thomas R. (1997). Defective neurite extension is caused by a mutation in amyloid β/A4 (Aβ) protein precursor found in familial Alzheimer’s disease. J. Neurobiol. 32 469– 480. 10.1002/(SICI)1097-4695(199705)32:5<469::AID-NEU3<3.0.CO;2-3 9110259 · DOI
  60. Lorent K. Overbergh L. Moechars D. de Strooper B. van Leuven F. van den Berghe H. (1995). Expression in mouse embryos and in adult mouse brain of three members of the amyloid precursor protein family, of the alpha-2-macroglobulin receptor/low density lipoprotein receptor-related protein and of its ligands apolipoprotein E, lipoprotein lipase. Neuroscience 65 1009– 1025. 10.1016/0306-4522(94)00555-J 7542371 · DOI
  61. Luo L. Tully T. White K. (1992). Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron 9 595– 605. 10.1016/0896-6273(92)90024-8 1389179 · DOI
  62. Magara F. Müller U. Li Z. W. Lipp H. P. Weissmann C. Stagljar M. (1999). Genetic background changes the pattern of forebrain commissure defects in transgenic mice underexpressing the beta-amyloid-precursor protein. Proc. Natl. Acad. Sci. U.S.A. 96 4656– 4661. 10.1073/pnas.96.8.4656 10200318 PMC16388 · DOI
  63. Menéndez-González M. Pérez-Pinera P. Martínez-Rivera M. Calatayud M. T. Blázquez Menes B. (2006). APP processing and the APP-KPI domain involvement in the amyloid cascade. Neuro. Dis. 2 277– 283. 10.1159/000092315 16909010 · DOI
  64. Milosch N. Tanriöver G. Kundu A. Rami A. François J.-C. Baumkötter F. (2014). Holo-APP and G-protein-mediated signaling are required for sAPPα-induced activation of the Akt survival pathway. Cell Death Dis. 5: e1391. 10.1038/cddis.2014.352 25165877 PMC4454324 · DOI
  65. Mitani Y. Yarimizu J. Saita K. Uchino H. Akashiba H. Shitaka Y. (2012). Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J. Neurosci. 32 2037– 2050. 10.1523/JNEUROSCI.4264-11.2012 22323718 PMC6621706 · DOI · Paper page
  66. Morales-Corraliza J. Mazzella M. J. Berger J. D. Diaz N. S. Choi J. H. K. Levy E. (2009). In vivo turnover of tau and APP metabolites in the brains of wild-type and Tg2576 mice: greater stability of sAPP in the beta-amyloid depositing mice. PLoS One 4: e7134– e7134. 10.1371/journal.pone.0007134 19771166 PMC2741602 · DOI
  67. Mucke L. Masliah E. Yu G. Q. Mallory M. Rockenstein E. M. Tatsuno G. (2000). High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20 4050– 4058. 10.1523/jneurosci.20-11-04050.2000 10818140 PMC6772621 · DOI · Paper page
  68. Müller T. Concannon C. G. Ward M. W. Walsh C. M. Tirniceriu A. L. Tribl F. (2007). Modulation of gene expression and cytoskeletal dynamics by the amyloid precursor protein intracellular domain (AICD). Mol. Biol. Cell 18 201– 210. 10.1091/mbc.e06-04-0283 17093061 PMC1751311 · DOI
  69. Muller U. Cristina N. Li Z.-W. Wolfer D. P. Lipp H.-P. Rulicke T. (1994). Behavioral and anatomical deficits in mice homozygous for a modified beta-amyloid precursor protein gene. Cell 79 755– 765. 10.1016/0092-8674(94)90066-3 8001115 · DOI
  70. Nalivaeva N. N. Turner A. J. (2013). The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett. 587 2046– 2054. 10.1016/j.febslet.2013.05.010 23684647 · DOI
  71. Nikolaev A. McLaughlin T. O’Leary D. D. M. Tessier-Lavigne M. (2009). APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457 981– 989. 10.1038/nature07767 19225519 PMC2677572 · DOI · Paper page
  72. O’Connor A. Pannee J. Poole T. Arber C. Portelius E. Swift I. J. (2021). Plasma amyloid-β ratios in autosomal dominant Alzheimer’s disease: the influence of genotype. Brain 144 2964– 2970. 10.1093/brain/awab166 33892504 PMC8634092 · DOI
  73. Opsomer R. Contino S. Perrin F. Gualdani R. Tasiaux B. Doyen P. (2020). Amyloid precursor protein (APP) controls the expression of the transcriptional activator neuronal PAS domain protein 4 (NPAS4) and synaptic GABA release. eNeuro 7: ENEURO.0322-19.2020. 10.1523/ENEURO.0322-19.2020 32327470 PMC7262005 · DOI
  74. Ott M. Bullock S. (2001). A gene trap insertion reveals that amyloid precursor protein expression is a very early event in murine embryogenesis. Dev. Genes Evol. 211 355– 357. 10.1007/s004270100158 11466532 · DOI
  75. Palmeri A. Ricciarelli R. Gulisano W. Rivera D. Rebosio C. Calcagno E. (2017). Amyloid-β peptide is needed for cgmp-induced long-term potentiation and memory. J. Neurosci. 37 6926– 6937. 10.1523/JNEUROSCI.3607-16.2017 28626017 PMC5518421 · DOI
  76. Penninkilampi R. Brothers H. M. Eslick G. D. (2017). Safety and efficacy of anti-amyloid-β immunotherapy in Alzheimer’s disease: a systematic review and meta-analysis. J. Neuro. Pharmacol. 12 194– 203. 10.1007/s11481-016-9722-5 28025724 · DOI
  77. Peric A. Annaert W. (2015). Early etiology of Alzheimer’s disease: tipping the balance toward autophagy or endosomal dysfunction? Acta Neuropathol. 129 363– 381. 10.1007/s00401-014-1379-7 25556159 PMC4331606 · DOI
  78. Peters-Libeu C. Campagna J. Mitsumori M. Poksay K. S. Spilman P. Sabogal A. (2015). sAβPPα is a potent endogenous inhibitor of BACE1. J. Alzheimers Dis. 47 545– 555. 10.3233/JAD-150282 26401691 · DOI
  79. Phinney A. L. Calhoun M. E. Wolfer D. P. Lipp H. P. Zheng H. Jucker M. (1999). No hippocampal neuron or synaptic bouton loss in learning-impaired aged β-amyloid precursor protein-null mice. Neuroscience 90 1207– 1216. 10.1016/S0306-4522(98)00645-9 10338291 · DOI
  80. Readhead B. Haure-Mirande J. V. Funk C. C. Richards M. A. Shannon P. Haroutunian V. (2018). Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron 99 64– 82.e7. 10.1016/j.neuron.2018.05.023 29937276 PMC6551233 · DOI · Paper page
  81. Rice H. C. Young-Pearse T. L. Selkoe D. J. (2013). Systematic evaluation of candidate ligands regulating ectodomain shedding of amyloid precursor protein. Biochemistry 52 3264– 3277. 10.1021/bi400165f 23597280 PMC3809327 · DOI
  82. Ring S. Weyer S. W. Kilian S. B. Waldron E. Pietrzik C. U. Filippov M. A. (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. Off. J. Soc. Neurosci. 27 7817– 7826. 10.1523/JNEUROSCI.1026-07.2007 17634375 PMC6672885 · DOI · Paper page
  83. Rovelet-Lecrux A. Hannequin D. Raux G. Le Meur N. Laquerrière A. Vital A. (2006). APP locus duplication causes autosomal dominant early-onset alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38 24– 26. 10.1038/ng1718 16369530 · DOI
  84. Ryan N. S. Nicholas J. M. Weston P. S. J. Liang Y. Lashley T. Guerreiro R. (2016). Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol. 15 1326– 1335. 10.1016/S1474-4422(16)30193-4 27777022 · DOI
  85. Sabo S. L. Ikin A. F. Buxbaum J. D. Greengard P. (2001). The alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J. Cell Biol. 153 1403– 1414. 10.1083/jcb.153.7.1403 11425871 PMC2150733 · DOI · Paper page
  86. Schon E. A. Area-Gomez E. (2013). Mitochondria-associated ER membranes in alzheimer disease. Mol. Cell. Neurosci. 55 26– 36. 10.1016/j.mcn.2012.07.011 22922446 · DOI · Paper page
  87. Seabrook G. R. Smith D. W. Bowery B. J. Easter A. Reynolds T. Fitzjohn S. M. (1999). Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38 349– 359. 10.1016/s0028-3908(98)00204-4 10219973 · DOI
  88. Senechal Y. Kelly P. H. Cryan J. F. Natt F. Dev K. K. (2007). Amyloid precursor protein knockdown by siRNA impairs spontaneous alternation in adult mice. J. Neurochem. 102 1928– 1940. 10.1111/j.1471-4159.2007.04672.x 17540010 · DOI
  89. Senechal Y. Larmet Y. Dev K. K. (2006). Unraveling in vivo functions of amyloid precursor protein: Insights from knockout and knockdown studies. Neuro. Dis. 3 134– 147. 10.1159/000094772 16954700 · DOI
  90. Sevigny J. Chiao P. Bussière T. Weinreb P. H. Williams L. Maier M. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537 50– 56. 10.1038/nature19323 27582220 · DOI · Paper page
  91. Shariati S. A. M. De Strooper B. (2013). Redundancy and divergence in the amyloid precursor protein family. FEBS Lett. 587 2036– 2045. 10.1016/j.febslet.2013.05.026 23707420 · DOI
  92. Sherrington R. Rogaev E. I. Liang Y. Rogaeva E. A. Levesque G. Ikeda M. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375 754– 760. 10.1038/375754a0 7596406 · DOI · Paper page
  93. Sleegers K. Brouwers N. Gijselinck I. Theuns J. Goossens D. Wauters J. (2006). APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 129 2977– 2983. 10.1093/brain/awl203 16921174 · DOI
  94. Smith P. Al Hashimi A. Girard J. Delay C. Hébert S. S. (2011). In vivo regulation of amyloid precursor protein neuronal splicing by microRNAs. J. Neurochem. 116 240– 247. 10.1111/j.1471-4159.2010.07097.x 21062284 · DOI
  95. Sosa L. J. Cáceres A. Dupraz S. Oksdath M. Quiroga S. Lorenzo A. (2017). The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system. J. Neurochem. 143 11– 29. 10.1111/jnc.14122 28677143 · DOI
  96. Stanga S. Zanou N. Audouard E. Tasiaux B. Contino S. Vandermeulen G. (2016). APP-dependent glial cell line-derived neurotrophic factor gene expression drives neuromuscular junction formation. FASEB J. 30 1696– 1711. 10.1096/fj.15-278739 26718890 · DOI
  97. Sugaya K. Chouinard M. Greene R. Robbins M. Personett D. Kent C. (1996). Molecular indices of neuronal and glial plasticity in the hippocampal formation in a rodent model of age-induced spatial learning impairment. J. Neurosci. 16 3427– 3443. 10.1523/jneurosci.16-10-03427.1996 8627377 PMC6579147 · DOI
  98. Tomita T. (2014). Molecular mechanism of intramembrane proteolysis by γ-secretase. J. Biochem. 156 195– 201. 10.1093/jb/mvu049 25108625 · DOI · Paper page
  99. Torroja L. Packard M. Gorczyca M. White K. Budnik V. (1999). The Drosophila-Amyloid Precursor Protein Homolog Promotes Synapse Differentiation at the Neuromuscular Junction. PMC6782486 10479682
  100. Tremml P. Lipp H. P. Müller U. Ricceri L. Wolfer D. P. (1998). Neurobehavioral development, adult openfield exploration and swimming navigation learning in mice with a modified beta-amyloid precursor protein gene. Behav. Brain Res. 95 65– 76. 10.1016/s0166-4328(97)00211-8 9754878 · DOI
  101. Vogl A. M. Phu L. Becerra R. Giusti S. A. Verschueren E. Hinkle T. B. (2020). Global site-specific neddylation profiling reveals that NEDDylated cofilin regulates actin dynamics. Nat. Struct. Mol. Biol. 27 210– 220. 10.1038/s41594-019-0370-3 32015554 · DOI
  102. von Koch C. S. Zheng H. Chen H. Trumbauer M. Thinakaran G. van der Ploeg L. H. (1997). Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol. Aging 18 661– 669. 10.1016/s0197-4580(97)00151-6 9461064 · DOI
  103. Wang B. Wang Z. Sun L. Yang L. Li H. Cole A. L. (2014). The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. J. Neurosci. 34 13314– 13325. 10.1523/JNEUROSCI.2848-14.2014 25274811 PMC4180470 · DOI
  104. Wang H. la Russa M. Qi L. S. (2016). CRISPR/Cas9 in genome editing and beyond. Ann. Rev. Biochem. 85 227– 264. 10.1146/annurev-biochem-060815-014607 27145843 PMC13384723 · DOI
  105. Wentzell J. S. Bolkan B. J. Carmine-Simmen K. Swanson T. L. Musashe D. T. Kretzschmar D. (2012). Amyloid precursor proteins are protective in Drosophila models of progressive neurodegeneration. Neurobiol. Dis. 46 78– 87. 10.1016/j.nbd.2011.12.047 22266106 PMC4073673 · DOI
  106. Wisniewski K. E. Wisniewski H. M. Wen G. Y. (1985). Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann. Neurol. 17 278– 282. 10.1002/ana.410170310 3158266 · DOI · Paper page
  107. Xinwei C. (2001). A transcriptively active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293 115– 120. 10.1126/science.1058783 11441186 · DOI · Paper page
  108. Yagi H. Irino M. Matsushita T. Katoh S. Umezawa M. Tsuboyama T. (1989). Spontaneous spongy degeneration of the brain stem in SAM-P/8 mice, a newly developed memory-deficient strain. J. Neuropathol. Exp. Neurol. 48 577– 590. 10.1097/00005072-198909000-00008 2769310 · DOI
  109. Yamamoto K. Miyoshi T. Yae T. Kawashima K. Araki H. Hanada K. (1994). The survival of rat cerebral cortical neurons in the presence of trophic APP peptides. J. Neurobiol. 25 585– 594. 10.1002/neu.480250510 8071662 · DOI
  110. Yan R. Vassar R. (2014). Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol. 13 319– 329. 10.1016/S1474-4422(13)70276-X 24556009 PMC4086426 · DOI
  111. Yang G. Gong Y. D. Gong K. Jiang W. L. Kwon E. Wang P. (2005). Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2. Neurosci. Lett. 384 66– 71. 10.1016/j.neulet.2005.04.040 15919150 · DOI
  112. Ye I. Y. Bassit B. Zhu L. Yang X. Wang C. Li Y. M. (2007). γ-secretase substrate concentration modulates the Aβ42/Aβ40 ratio: implications for alzheimer disease. J. Biol. Chem. 282 23639– 23644. 10.1074/jbc.M704601200 17556361 · DOI
  113. Young-Pearse T. L. Chen A. C. Chang R. Marquez C. Selkoe D. J. (2008). Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1. Neural Dev. 3: 15. 10.1186/1749-8104-3-15 18573216 PMC2442059 · DOI · Paper page
  114. Yu Y. Logovinsky V. Schuck E. Kaplow J. Chang M. K. Miyagawa T. (2014). Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ-secretase modulator, E2212, in healthy human subjects. J. Clin. Pharmacol. 54 528– 536. 10.1002/jcph.249 24343761 · DOI
  115. Zheng H. Jiang M. Trumbauer M. E. Sirinathsinghji D. J. S. Hopkins R. Smith D. W. (1995). beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81 525– 531. 10.1016/0092-8674(95)90073-x 7758106 · DOI

Cited by

Sorted by citations

Authors
Gabriele, R. M. C., Abel, E., Fox, N. C., Wray, S., & Arber, C.
Affiliations
  • UCL Queen Square Institute of Neurology (GB)
  • UK Dementia Research Institute (GB)
Corresponding author
Arber, Charles
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2022-03-14
Volume
16
Pages
835645-835645
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2022.835645
PMC
PMC8964081
OpenAlex
W4221113970
Cited by
44
References
13
Citations by year
2026: 13 · 2025: 7 · 2024: 17 · 2023: 5 · 2022: 2
FWCI
1.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Alzheimer's Society ((AS-JF- 18-008)
  • Medical Research Centre (MR/M02492X/1, MC_U12266B)
  • Alzheimer’s Research UK (ARUK-SRF2016B-2)
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, Alzheimer's disease, APP processing, disease-modifying therapy

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