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Cited by 45Alzheimer's disease research and treatmentsMitochondrial Function and PathologyAutophagy in Disease and Therapy

Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta

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Lopez Sanchez, M. Isabel G., Waugh, Hayley S., Tsatsanis, Andrew, Wong, Bruce X., Crowston, Jonathan G., Duce, James A., Trounce, Ian A.·2017·Scientific Reports
DOI 10.1038/s41598-017-10233-0PMC PMC5574989
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Abstract

Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPα) play important physiological and neuroprotective roles. However, rare forms of familial Alzheimer’s disease are associated with mutations in APP that increase toxic amyloidogenic cleavage of APP and produce amyloid beta (Aβ) at the expense of sAPPα and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between Aβ and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or Aβ on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not Aβ, profoundly decreased respiration and enhanced glycolysis, while mitochondrial DNA (mtDNA) transcripts were decreased, without detrimental effects to cell growth. These effects cannot be ascribed to Aβ toxicity, since higher levels of endogenous Aβ in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of β-secretase decreased mitochondrial respiration, suggesting that non-amyloidogenic processing of APP may be responsible for mitochondrial changes. Our results have two important implications, the need for caution in the interpretation of mitochondrial perturbations in models where APP is overexpressed, and a potential role of sAPPα or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism.

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  • Accumulation and processing of APP lead to mitophagic changes in neurons.

    “APP is expressed and processed in T-cells at low levels (26) – accumulation and processing of APP lead to mitophagic changes in neurons (27).”

    From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [27]

    The Introduction (page unavailable) says the study tested increased neuronal APP expression and mitochondrial metabolism in SH-SY5Y neuroblastoma cells; the Discussion (page unavailable) describes APP-associated down-regulation of oxidative phosphorylation. These passages support mitochondrial metabolic changes associated with APP, but they do not report mitophagy, and the studied cells are not neurons themselves. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • APP is directly involved in the inhibition of mitophagy.

    “It is directly involved in the inhibition of mitophagy (27,39), which was seen in the tumor-infiltrating lymphocytes in both in vivo tumor models (Figure 1).”

    From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [27]

    The Results and Discussion report that increased APP reduces mitochondrial respiration and oxidative phosphorylation in neuroblastoma cells. Searches for mitophagy inhibition and mitochondrial clearance found no passage addressing whether APP inhibits mitophagy; reduced respiration does not establish that claim. Page numbers are unavailable in our copy. (LLM, conf=0.76)

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Research works printed but not linked: 55

  1. [1]Plummer S den Heuvel V Thornton C Corrigan EF Cappai R The Neuroprotective Properties of the Amyloid Precursor Protein Following Traumatic Brain Injury Aging Dis 2016 7 163 179 10.14336/AD.2015.0907 27114849 PMC4809608 · DOI
  2. [2]Kogel D Deller T Behl C Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging Exp Brain Res 2012 217 471 479 10.1007/s00221-011-2932-4 22086493 · DOI
  3. [3]Corrigan F The neuroprotective activity of the amyloid precursor protein against traumatic brain injury is mediated via the heparin binding site in residues 96-110 Journal of neurochemistry 2014 128 196 204 10.1111/jnc.12391 23919582 · DOI
  4. [4]Clarke J Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats Eur J Neurosci 2007 26 1845 1852 10.1111/j.1460-9568.2007.05807.x 17897395 · DOI · Paper page
  5. [5]Ayton S Ceruloplasmin and beta-amyloid precursor protein confer neuroprotection in traumatic brain injury and lower neuronal iron Free Radic Biol Med 2014 69 331 337 10.1016/j.freeradbiomed.2014.01.041 24509156 · DOI
  6. [6]Kojro E Fahrenholz F The non-amyloidogenic pathway: structure and function of alpha-secretases Subcell Biochem 2005 38 105 127 10.1007/0-387-23226-5_5 15709475 · DOI
  7. [7]Haass C Hung AY Schlossmacher MG Teplow DB Selkoe DJ Beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms J Biol Chem 1993 268 3021 3024 8428976
  8. [8]Esch FS Cleavage of amyloid beta peptide during constitutive processing of its precursor Science 1990 248 1122 1124 10.1126/science.2111583 2111583 · DOI
  9. [9]Bour A Little S Dodart JC Kelche C Mathis C A secreted form of the beta-amyloid precursor protein (sAPP695) improves spatial recognition memory in OF1 mice Neurobiol Learn Mem 2004 81 27 38 10.1016/S1074-7427(03)00071-6 14670356 · DOI
  10. [10]Corrigan F sAPPalpha rescues deficits in amyloid precursor protein knockout mice following focal traumatic brain injury Journal of neurochemistry 2012 122 208 220 10.1111/j.1471-4159.2012.07761.x 22519988 · DOI
  11. [11]Taylor CJ Endogenous secreted amyloid precursor protein-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory Neurobiol Dis 2008 31 250 260 10.1016/j.nbd.2008.04.011 18585048 · DOI
  12. [12]Thornton E Vink R Blumbergs PC Van Den Heuvel C Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats Brain research 2006 1094 38 46 10.1016/j.brainres.2006.03.107 16697978 · DOI
  13. [13]Milosch N Holo-APP and G-protein-mediated signaling are required for sAPPalpha-induced activation of the Akt survival pathway Cell Death Dis 2014 5 10.1038/cddis.2014.352 25165877 PMC4454324 · DOI
  14. [14]Gralle M Botelho MG Wouters FS Neuroprotective secreted amyloid precursor protein acts by disrupting amyloid precursor protein dimers J Biol Chem 2009 284 15016 15025 10.1074/jbc.M808755200 19336403 PMC2685684 · DOI
  15. [15]Goodman Y Mattson MP Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury Experimental neurology 1994 128 1 12 10.1006/exnr.1994.1107 8070512 · DOI
  16. [16]Schubert D Behl C The expression of amyloid beta protein precursor protects nerve cells from beta-amyloid and glutamate toxicity and alters their interaction with the extracellular matrix Brain Res 1993 629 275 282 10.1016/0006-8993(93)91331-L 7906601 · DOI
  17. [17]Vassar R Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE Science 1999 286 735 741 10.1126/science.286.5440.735 10531052 · DOI · Paper page
  18. [18]Jarrett JT Berger EP Lansbury PT Jr. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease Biochemistry 1993 32 4693 4697 10.1021/bi00069a001 8490014 · DOI · Paper page
  19. [19]Mann DM Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer’s disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene The American journal of pathology 1996 148 1257 1266 8644866 PMC1861527
  20. [21]Cardoso SM Santana I Swerdlow RH Oliveira CR Mitochondria dysfunction of Alzheimer’s disease cybrids enhances Abeta toxicity J Neurochem 2004 89 1417 1426 10.1111/j.1471-4159.2004.02438.x 15189344 · DOI
  21. [22]Wang X Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins Proceedings of the National Academy of Sciences of the United States of America 2008 105 19318 19323 10.1073/pnas.0804871105 19050078 PMC2614759 · DOI · Paper page
  22. [24]Krako N Characterization of mitochondrial dysfunction in the 7PA2 cell model of Alzheimer’s disease J Alzheimers Dis 2013 37 747 758 23948918
  23. [25]Morais VA De Strooper B Mitochondria dysfunction and neurodegenerative disorders: cause or consequence J Alzheimers Dis 2010 20 Suppl 2 S255 263 10.3233/JAD-2010-100345 20463408 · DOI
  24. [26]Rhein V Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma cells Cell Mol Neurobiol 2009 29 1063 1071 10.1007/s10571-009-9398-y 19350381 PMC11506282 · DOI
  25. [27]Kozera B Rapacz M Reference genes in real-time PCR J Appl Genet 2013 54 391 406 10.1007/s13353-013-0173-x 24078518 PMC3825189 · DOI
  26. [28]Trounce I Neill S Wallace DC Cytoplasmic transfer of the mtDNA nt 8993 T– > G (ATP6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates cosegregation with a decrease in state III respiration and ADP/O ratio Proceedings of the National Academy of Sciences of the United States of America 1994 91 8334 8338 10.1073/pnas.91.18.8334 8078883 PMC44600 · DOI
  27. [29]Sanchez MI RNA processing in human mitochondria Cell Cycle 2011 10 2904 2916 10.4161/cc.10.17.17060 21857155 · DOI
  28. [30]Rackham O Mercer TR Filipovska A The human mitochondrial transcriptome and the RNA-binding proteins that regulate its expression Wiley Interdiscip Rev RNA 2012 3 675 695 10.1002/wrna.1128 22777840 · DOI
  29. [31]Rhein V Ginkgo biloba extract ameliorates oxidative phosphorylation performance and rescues abeta-induced failure PloS one 2010 5 10.1371/journal.pone.0012359 20808761 PMC2927422 · DOI
  30. [33]Forman MS Cook DG Leight S Doms RW Lee VM Differential effects of the swedish mutant amyloid precursor protein on beta-amyloid accumulation and secretion in neurons and nonneuronal cells J Biol Chem 1997 272 32247 32253 10.1074/jbc.272.51.32247 9405428 · DOI
  31. [34]Yang TT Hsu CT Kuo YM Amyloid precursor protein, heat-shock proteins, and Bcl-2 form a complex in mitochondria and modulate mitochondria function and apoptosis in N2a cells Mech Ageing Dev 2009 130 592 601 10.1016/j.mad.2009.07.002 19622370 · DOI
  32. [35]Belyaev ND The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a {beta}-secretase-dependent pathway J Biol Chem 2010 285 41443 41454 10.1074/jbc.M110.141390 20961856 PMC3009870 · DOI
  33. [36]Mutisya EM Bowling AC Beal MF Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease J Neurochem 1994 63 2179 2184 10.1046/j.1471-4159.1994.63062179.x 7964738 · DOI
  34. [37]Kish SJ Brain cytochrome oxidase in Alzheimer’s disease J Neurochem 1992 59 776 779 10.1111/j.1471-4159.1992.tb09439.x 1321237 · DOI · Paper page
  35. [39]Kish SJ Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer’s disease and in hereditary spinocerebellar ataxia disorders: a nonspecific change? J Neurochem 1999 72 700 707 10.1046/j.1471-4159.1999.0720700.x 9930743 · DOI
  36. [40]Parks JK Smith TS Trimmer PA Bennett JP Jr. Parker WD Jr. Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro J Neurochem 2001 76 1050 1056 10.1046/j.1471-4159.2001.00112.x 11181824 · DOI
  37. [42]Hauptmann S Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice Neurobiol Aging 2009 30 1574 1586 10.1016/j.neurobiolaging.2007.12.005 18295378 · DOI · Paper page
  38. [43]Keil U Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis J Biol Chem 2004 279 50310 50320 10.1074/jbc.M405600200 15371443 · DOI · Paper page
  39. [44]Haass C Kaether C Thinakaran G Sisodia S Trafficking and proteolytic processing of APP Cold Spring Harb Perspect Med 2012 2 10.1101/cshperspect.a006270 22553493 PMC3331683 · DOI · Paper page
  40. [46]Reddy PH Beal MF Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease Trends Mol Med 2008 14 45 53 10.1016/j.molmed.2007.12.002 18218341 PMC3107703 · DOI · Paper page
  41. [47]Manczak M Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression Hum Mol Genet 2006 15 1437 1449 10.1093/hmg/ddl066 16551656 · DOI · Paper page
  42. [48]Schaefer PM von Einem B Walther P Calzia E von Arnim CA Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration PLoS One 2016 11 10.1371/journal.pone.0168157 28005987 PMC5178995 · DOI
  43. [49]Murphy MP How mitochondria produce reactive oxygen species The Biochemical journal 2009 417 1 13 10.1042/BJ20081386 19061483 PMC2605959 · DOI · Paper page
  44. [50]Ray PD Huang BW Tsuji Y Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling Cell Signal 2012 24 981 990 10.1016/j.cellsig.2012.01.008 22286106 PMC3454471 · DOI · Paper page
  45. [51]Shukla V Mishra SK Pant HC Oxidative stress in neurodegeneration Adv Pharmacol Sci 2011 2011 21941533 PMC3177364
  46. [52]Lopez Sanchez, M. I., Crowston, J. G., Mackey, D. A. & Trounce, I. A. Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies. Pharmacol Ther, doi:10.1016/j.pharmthera.2016.06.004 (2016). 27288727 · DOI
  47. [53]Itoh T Expression of amyloid precursor protein after rat traumatic brain injury Neurol Res 2009 31 103 109 10.1179/016164108X323771 19228461 · DOI · Paper page
  48. [54]Harkany T Increased amyloid precursor protein expression and serotonergic sprouting following excitotoxic lesion of the rat magnocellular nucleus basalis: neuroprotection by Ca(2+) antagonist nimodipine Neuroscience 2000 101 101 114 10.1016/S0306-4522(00)00296-7 11068140 · DOI
  49. [57]Sanchez MI Estrogen-mediated regulation of mitochondrial gene expression Mol Endocrinol 2015 29 14 27 10.1210/me.2014-1077 25375021 PMC5414768 · DOI
  50. [58]Van Bergen NJ Blake RE Crowston JG Trounce IA Oxidative phosphorylation measurement in cell lines and tissues Mitochondrion 2014 15 24 33 10.1016/j.mito.2014.03.003 24657935 · DOI
  51. [59]Trounce IA Kim YL Jun AS Wallace DC Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines Methods in enzymology 1996 264 484 509 10.1016/S0076-6879(96)64044-0 8965721 · DOI
  52. [60]Holloszy JO Oscai LB Don IJ Mole PA Mitochondrial citric acid cycle and related enzymes: adaptive response to exercise Biochem Biophys Res Commun 1970 40 1368 1373 10.1016/0006-291X(70)90017-3 4327015 · DOI
  53. [61]Williams RS Salmons S Newsholme EA Kaufman RE Mellor J Regulation of nuclear and mitochondrial gene expression by contractile activity in skeletal muscle J Biol Chem 1986 261 376 380 3941082
  54. [62]Lim SC Loss of mitochondrial DNA-encoded protein ND1 results in disruption of complex I biogenesis during early stages of assembly FASEB J 2016 30 2236 2248 10.1096/fj.201500137R 26929434 · DOI
  55. [63]Livak KJ Schmittgen TD Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method Methods 2001 25 402 408 10.1006/meth.2001.1262 11846609 · DOI · Paper page

Cited by

Sorted by citations

Authors
Lopez Sanchez, M. I. G., Waugh, H. S., Tsatsanis, A., Wong, B. X., Crowston, J. G., Duce, J. A., & Trounce, I. A.
Affiliations
  • The University of Melbourne (AU)
  • University of Leeds (GB)
Corresponding author
Trounce, Ian A.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-08-29
Volume
7
Issue
1
Pages
9835-9835
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-10233-0
PMC
PMC5574989
OpenAlex
W2749464428
Cited by
45
References
8
Citations by year
2026: 6 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 9 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 3
FWCI
2.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • BrightFocus Foundation (G2009020)
  • State Government of Victoria
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
amyloid precursor protein, soluble APP alpha, amyloid-beta, mitochondrial oxidative phosphorylation, mitochondrial respiration, mitochondrial transcription, glycolysis, beta-secretase inhibition, Alzheimer's disease, mitochondrial dysfunction, neuronal metabolism
MeSH terms
Alzheimer Disease, Cell Line, Electron Transport Complex IV, Enzyme Activation, Glycolysis, Humans, Mitochondria, Mutation, Neurons, Oxidative Phosphorylation, Transcription, Genetic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Gene Dosage, Cell Respiration, Genes, Mitochondrial, Amyloid Precursor Protein Secretases

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