CoChat
Sign Up
Cited by 172Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent

Open access
Puzzo, Daniela, Piacentini, Roberto, Fá, Mauro, Gulisano, Walter, Li Puma, Domenica D, Staniszewski, Agnes, Zhang, Hong, Tropea, Maria Rosaria +6 more·2017·eLife
DOI 10.7554/elife.26991PMC PMC5529106
Open this paper in CoChat — free account

Abstract

The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oAβ) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oAβ and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oAβ, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oAβ and oTau requires expression of APP. Finally, the toxic effect of both extracellular oAβ and oTau on memory and LTP is dependent upon APP since APP-KO mice were resistant to oAβ- and oTau-induced defects in spatial/associative memory and LTP. Thus, APP might serve as a common therapeutic target against Alzheimer's Disease (AD) and a host of other neurodegenerative diseases characterized by abnormal levels of Aβ and/or Tau.

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 · 10.7554/elife.26991

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.

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 67 · Cited by 172

Research works printed but not linked: 59

  1. Bakker A Krauss GL Albert MS Speck CL Jones LR Stark CE Yassa MA Bassett SS Shelton AL Gallagher M 2012 Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment Neuron 74 467 474 10.1016/j.neuron.2012.03.023 22578498 PMC3351697 · DOI
  2. Banks WA Kastin AJ Maness LM Huang W Jaspan JB 1995 Permeability of the blood-brain barrier to amylin Life Sciences 57 1993 2001 10.1016/0024-3205(95)02197-Q 7475950 · DOI
  3. Bliss TV Collingridge GL 1993 A synaptic model of memory: long-term potentiation in the hippocampus Nature 361 31 39 10.1038/361031a0 8421494 · DOI · Paper page
  4. Busche MA Chen X Henning HA Reichwald J Staufenbiel M Sakmann B Konnerth A 2012 Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease PNAS 109 8740 8745 10.1073/pnas.1206171109 22592800 PMC3365221 · DOI · Paper page
  5. Cao X Südhof TC 2001 A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60 Science 293 115 120 10.1126/science.1058783 11441186 · DOI · Paper page
  6. Cappai R Cheng F Ciccotosto GD Needham BE Masters CL Multhaup G Fransson LA Mani K 2005 The amyloid precursor protein (APP) of alzheimer disease and its paralog, APLP2, modulate the cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo Journal of Biological Chemistry 280 13913 13920 10.1074/jbc.M409179200 15677459 · DOI
  7. Cizas P Budvytyte R Morkuniene R Moldovan R Broccio M Lösche M Niaura G Valincius G Borutaite V 2010 Size-dependent neurotoxicity of beta-amyloid oligomers Archives of Biochemistry and Biophysics 496 84 92 10.1016/j.abb.2010.02.001 20153288 PMC2853175 · DOI
  8. Cole SL Vassar R 2007 The Alzheimer's disease beta-secretase enzyme, BACE1 Molecular Neurodegeneration 2 22 10.1186/1750-1326-2-22 18005427 PMC2211305 · DOI · Paper page
  9. De Strooper B 2007 Loss-of-function presenilin mutations in alzheimer disease. talking point on the role of presenilin mutations in alzheimer disease EMBO Reports 8 141 146 10.1038/sj.embor.7400897 17268505 PMC1796779 · DOI
  10. Del Prete D Lombino F Liu X D'Adamio L 2014 APP is cleaved by Bace1 in pre-synaptic vesicles and establishes a pre-synaptic interactome, via its intracellular domain, with molecular complexes that regulate pre-synaptic vesicles functions PLoS One 9 e108576 10.1371/journal.pone.0108576 25247712 PMC4172690 · DOI
  11. Deyts C Thinakaran G Parent AT 2016 APP receptor? to be or not to be Trends in Pharmacological Sciences 37 390 411 10.1016/j.tips.2016.01.005 26837733 PMC4846520 · DOI
  12. Fiorito J Saeed F Zhang H Staniszewski A Feng Y Francis YI Rao S Thakkar DM Deng SX Landry DW Arancio O 2013 Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease European Journal of Medicinal Chemistry 60 285 294 10.1016/j.ejmech.2012.12.009 23313637 PMC3582828 · DOI
  13. Fraser SP Suh YH Chong YH Djamgoz MB 1996 Membrane currents induced in xenopus oocytes by the C-terminal fragment of the beta-amyloid precursor protein Journal of Neurochemistry 66 2034 2040 10.1046/j.1471-4159.1996.66052034.x 8780033 · DOI
  14. Fraser SP Suh YH Djamgoz MB 1997 Ionic effects of the Alzheimer's disease beta-amyloid precursor protein and its metabolic fragments Trends in Neurosciences 20 67 72 10.1016/S0166-2236(96)10079-5 9023874 · DOI
  15. Fá M Puzzo D Piacentini R Staniszewski A Zhang H Baltrons MA Li Puma DD Chatterjee I Li J Saeed F Berman HL Ripoli C Gulisano W Gonzalez J Tian H Costa JA Lopez P Davidowitz E Yu WH Haroutunian V Brown LM Palmeri A Sigurdsson EM Duff KE Teich AF Honig LS Sierks M Moe JG D'Adamio L Grassi C Kanaan NM Fraser PE Arancio O 2016 Extracellular tau oligomers produce an Immediate impairment of LTP and memory Scientific Reports 6 19393 10.1038/srep19393 26786552 PMC4726138 · DOI
  16. Gendreau KL Hall GF Tangles HGF 2013 Tangles, toxicity, and Tau secretion in AD - New Approaches to a Vexing Problem Frontiers in Neurology 4 160 10.3389/fneur.2013.00160 24151487 PMC3801151 · DOI
  17. Giaccone G Pedrotti B Migheli A Verga L Perez J Racagni G Smith MA Perry G De Gioia L Selvaggini C Salmona M Ghiso J Frangione B Islam K Bugiani O Tagliavini F beta PP 1996 Beta PP and tau interaction. A possible link between amyloid and neurofibrillary tangles in Alzheimer's disease The American Journal of Pathology 148 79 87 8546229 PMC1861592
  18. Hölttä M Hansson O Andreasson U Hertze J Minthon L Nägga K Andreasen N Zetterberg H Blennow K 2013 Evaluating amyloid-β oligomers in cerebrospinal fluid as a biomarker for alzheimer's disease PLoS One 8 e66381 10.1371/journal.pone.0066381 23799095 PMC3682966 · DOI
  19. Irvine GB El-Agnaf OM Shankar GM Walsh DM 2008 Protein aggregation in the brain: the molecular basis for alzheimer's and Parkinson's diseases Molecular Medicine 14 1 64 10.2119/2007-00100.Irvine 18368143 PMC2274891 · DOI
  20. Islam K Levy E 1997 Carboxyl-terminal fragments of beta-amyloid precursor protein bind to microtubules and the associated protein tau The American Journal of Pathology 151 265 271 9212751 PMC1857905
  21. Jhamandas JH Li Z Westaway D Yang J Jassar S MacTavish D 2011 Actions of β-amyloid protein on human neurons are expressed through the amylin receptor The American Journal of Pathology 178 140 149 10.1016/j.ajpath.2010.11.022 21224052 PMC3070588 · DOI
  22. 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 10.1016/S0896-6273(03)00124-7 12670422 · DOI · Paper page
  23. Kayed R Sokolov Y Edmonds B McIntire TM Milton SC Hall JE Glabe CG 2004 Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases Journal of Biological Chemistry 279 46363 46366 10.1074/jbc.C400260200 15385542 · DOI
  24. Kimura R MacTavish D Yang J Westaway D Jhamandas JH 2012 Beta amyloid-induced depression of hippocampal long-term potentiation is mediated through the amylin receptor Journal of Neuroscience 32 17401 17406 10.1523/JNEUROSCI.3028-12.2012 23197731 PMC6621862 · DOI
  25. Kopeikina KJ Hyman BT Spires-Jones TL 2012 Soluble forms of tau are toxic in Alzheimer's disease Translational Neuroscience 3 223 233 10.2478/s13380-012-0032-y 23029602 PMC3460520 · DOI · Paper page
  26. Koppensteiner P Trinchese F Fà M Puzzo D Gulisano W Yan S Poussin A Liu S Orozco I Dale E Teich AF Palmeri A Ninan I Boehm S Arancio O Wì G Sì Y Aì P Sì L Eì D AFì T 2016 Time-dependent reversal of synaptic plasticity induced by physiological concentrations of oligomeric aβ42: an early index of alzheimer's disease Scientific Reports 6 32553 10.1038/srep32553 27581852 PMC5007504 · DOI
  27. Lai AY McLaurin J 2010 Mechanisms of amyloid-Beta Peptide uptake by neurons: the role of lipid rafts and lipid raft-associated proteins International Journal of Alzheimer's Disease 2011 548380 10.4061/2011/548380 21197446 PMC3010653 · DOI
  28. Lasagna-Reeves CA Castillo-Carranza DL Guerrero-Muoz MJ Jackson GR Kayed R 2010 Preparation and characterization of neurotoxic tau oligomers Biochemistry 49 10039 10041 10.1021/bi1016233 21047142 · DOI · Paper page
  29. Lasagna-Reeves CA Castillo-Carranza DL Sengupta U Guerrero-Munoz MJ Kiritoshi T Neugebauer V Jackson GR Kayed R 2012 Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau Scientific Reports 2 700 10.1038/srep00700 23050084 PMC3463004 · DOI · Paper page
  30. Lindahl U Li JP Jp L 2009 Interactions between heparan sulfate and proteins-design and functional implications International Review of Cell and Molecular Biology 276 105 159 10.1016/S1937-6448(09)76003-4 19584012 · DOI
  31. Lombino F Biundo F Tamayev R Arancio O D'Adamio L 2013 An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss PLoS One 8 e57120 10.1371/journal.pone.0057120 23451158 PMC3579798 · DOI
  32. Luo Y Bolon B Kahn S Bennett BD Babu-Khan S Denis P Fan W Kha H Zhang J Gong Y Martin L Louis JC Yan Q Richards WG Citron M Vassar R 2001 Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation Nature Neuroscience 4 231 232 10.1038/85059 11224535 · DOI · Paper page
  33. Mathews PM Jiang Y Schmidt SD Grbovic OM Mercken M Nixon RA 2002 Calpain activity regulates the cell surface distribution of amyloid precursor protein. inhibition of calpains enhances endosomal generation of beta-cleaved C-terminal APP fragments The Journal of Biological Chemistry 277 36415 36424 10.1074/jbc.M205208200 12087104 · DOI
  34. Mirbaha H Holmes BB Sanders DW Bieschke J Diamond MI 2015 Tau Trimers are the minimal propagation unit spontaneously internalized to seed intracellular aggregation Journal of Biological Chemistry 290 14893 14903 10.1074/jbc.M115.652693 25887395 PMC4463437 · DOI · Paper page
  35. Müller UC Zheng H 2012 Physiological functions of APP family proteins Cold Spring Harbor Perspectives in Medicine 2 a006288 10.1101/cshperspect.a006288 22355794 PMC3281588 · DOI
  36. Nordstedt C Caporaso GL Thyberg J Gandy SE Greengard P 1993 Identification of the alzheimer beta/A4 amyloid precursor protein in clathrin-coated vesicles purified from PC12 cells The Journal of Biological Chemistry 268 608 612 8416966
  37. Palop JJ Chin J Roberson ED Wang J Thwin MT Bien-Ly N Yoo J Ho KO Yu GQ Kreitzer A Finkbeiner S Noebels JL Mucke L 2007 Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease Neuron 55 697 711 10.1016/j.neuron.2007.07.025 17785178 PMC8055171 · DOI · Paper page
  38. Piacentini R Li Puma DD Ripoli C Marcocci ME De Chiara G Garaci E Palamara AT Grassi C 2015 Herpes Simplex virus type-1 infection induces synaptic dysfunction in cultured cortical neurons via GSK-3 activation and intraneuronal amyloid-β protein accumulation Scientific Reports 5 15444 10.1038/srep15444 26487282 PMC4614347 · DOI
  39. Pooler AM Phillips EC Lau DH Noble W Hanger DP 2013 Physiological release of endogenous tau is stimulated by neuronal activity EMBO Reports 14 389 394 10.1038/embor.2013.15 23412472 PMC3615658 · DOI · Paper page
  40. Puzzo D Lee L Palmeri A Calabrese G Arancio O 2014 Behavioral assays with mouse models of Alzheimer's disease: practical considerations and guidelines Biochemical Pharmacology 88 450 467 10.1016/j.bcp.2014.01.011 24462904 PMC4014001 · DOI
  41. Puzzo D Vitolo O Trinchese F Jacob JP Palmeri A Arancio O 2005 Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity Journal of Neuroscience 25 6887 6897 10.1523/JNEUROSCI.5291-04.2005 16033898 PMC6725343 · DOI
  42. Reinhard C Borgers M David G De Strooper B 2013 Soluble amyloid-β precursor protein binds its cell surface receptor in a cooperative fashion with glypican and syndecan proteoglycans Journal of Cell Science 126 4856 4861 10.1242/jcs.137919 23986479 · DOI
  43. Ripoli C Cocco S Li Puma DD Piacentini R Mastrodonato A Scala F Puzzo D D'Ascenzo M Grassi C 2014 Intracellular accumulation of amyloid-β (Aβ) protein plays a Major role in Aβ-induced alterations of glutamatergic synaptic transmission and plasticity Journal of Neuroscience 34 12893 12903 10.1523/JNEUROSCI.1201-14.2014 25232124 PMC6705320 · DOI
  44. Ripoli C Piacentini R Riccardi E Leone L Li Puma DD Bitan G Grassi C 2013 Effects of different amyloid β-protein analogues on synaptic function Neurobiology of Aging 34 1032 1044 10.1016/j.neurobiolaging.2012.06.027 23046860 · DOI
  45. Sandwall E O'Callaghan P Zhang X Lindahl U Lannfelt L Li JP Jp L 2010 Heparan sulfate mediates amyloid-beta internalization and cytotoxicity Glycobiology 20 533 541 10.1093/glycob/cwp205 20053627 · DOI
  46. Scala F Fusco S Ripoli C Piacentini R Li Puma DD Spinelli M Laezza F Grassi C D'Ascenzo M 2015 Intraneuronal aβ accumulation induces hippocampal neuron hyperexcitability through A-type K(+) current inhibition mediated by activation of caspases and GSK-3 Neurobiology of Aging 36 886 900 10.1016/j.neurobiolaging.2014.10.034 25541422 PMC4801354 · DOI
  47. Selkoe DJ 2008 Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior Behavioural Brain Research 192 106 113 10.1016/j.bbr.2008.02.016 18359102 PMC2601528 · DOI · Paper page
  48. Senechal Y Kelly PH Dev KK 2008 Amyloid precursor protein knockout mice show age-dependent deficits in passive avoidance learning Behavioural Brain Research 186 126 132 10.1016/j.bbr.2007.08.003 17884188 · DOI
  49. Shelkovnikova TA Kulikova AA Tsvetkov PO Peters O Bachurin SO Buchman VL Ninkina NN Proteinopathies NNN 2012 Proteinopathies, neurodegenerative disorders with protein aggregation-based pathology Molecular Biology 46 362 374 10.1134/S0026893312020161 22888630 · DOI
  50. Smith MA Siedlak SL Richey PL Mulvihill P Ghiso J Frangione B Tagliavini F Giaccone G Bugiani O Praprotnik D Kalaria RN Perry G 1995 Tau protein directly interacts with the amyloid beta-protein precursor: implications for alzheimer's disease Nature Medicine 1 365 369 10.1038/nm0495-365 7585068 · DOI
  51. Takahashi M Miyata H Kametani F Nonaka T Akiyama H Hisanaga S Hasegawa M 2015 Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau Acta Neuropathologica 129 895 907 10.1007/s00401-015-1415-2 25869641 PMC4436700 · DOI
  52. Takalo M Salminen A Soininen H Hiltunen M Haapasalo A 2013 Protein aggregation and degradation mechanisms in neurodegenerative diseases American Journal of Neurodegenerative Disease 2 1 14 23516262 PMC3601466
  53. Van Nostrand WE Melchor JP Keane DM Saporito-Irwin SM Romanov G Davis J Xu F 2002 Localization of a fibrillar amyloid beta-protein binding domain on its precursor Journal of Biological Chemistry 277 36392 36398 10.1074/jbc.M204676200 12107175 · DOI
  54. Verret L Mann EO Hang GB Barth AM Cobos I Ho K Devidze N Masliah E Kreitzer AC Mody I Mucke L Palop JJ 2012 Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in alzheimer model Cell 149 708 721 10.1016/j.cell.2012.02.046 22541439 PMC3375906 · DOI · Paper page
  55. Vossel KA Beagle AJ Rabinovici GD Shu H Lee SE Naasan G Hegde M Cornes SB Henry ML Nelson AB Seeley WW Geschwind MD Gorno-Tempini ML Shih T Kirsch HE Garcia PA Miller BL Mucke L 2013 Seizures and epileptiform activity in the early stages of alzheimer disease JAMA Neurology 70 1158 1166 10.1001/jamaneurol.2013.136 23835471 PMC4013391 · DOI
  56. Wineman-Fisher V Tudorachi L Nissim E Miller Y 2016 The removal of disulfide bonds in amylin oligomers leads to the conformational change of the 'native' amylin oligomers Physical Chemistry Chemical Physics 18 12438 12442 10.1039/C6CP01196A 27109452 · DOI
  57. Wu JW Herman M Liu L Simoes S Acker CM Figueroa H Steinberg JI Margittai M Kayed R Zurzolo C Di Paolo G Duff KE 2013 Small misfolded tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons The Journal of Biological Chemistry 288 1856 1870 10.1074/jbc.M112.394528 23188818 PMC3548495 · DOI · Paper page
  58. Wu Y Li Q Chen XZ 2007 Detecting protein-protein interactions by far western blotting Nature Protocols 2 3278 3284 10.1038/nprot.2007.459 18079728 · DOI
  59. Yamada K Holth JK Liao F Stewart FR Mahan TE Jiang H Cirrito JR Patel TK Hochgräfe K Mandelkow EM Holtzman DM 2014 Neuronal activity regulates extracellular tau in vivo The Journal of Experimental Medicine 211 387 393 10.1084/jem.20131685 24534188 PMC3949564 · DOI

Authors
Puzzo, D., Piacentini, R., Fá, M., Gulisano, W., Li Puma, D. D., Staniszewski, A., Zhang, H., Tropea, M. R., Cocco, S., Palmeri, A., Fraser, P., D'Adamio, L., Grassi, C., & Arancio, O.
Affiliations
  • University of Catania (IT)
  • Università Cattolica del Sacro Cuore (IT)
  • Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, United States
  • Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy
  • Columbia University Irving Medical Center (US)
  • University of Toronto (CA)
  • Albert Einstein College of Medicine (US)
Corresponding author
Arancio, Ottavio
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2017-07-11
Volume
6
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.26991
PMC
PMC5529106
OpenAlex
W2735082025
Cited by
172
References
67
Citations by year
2026: 5 · 2025: 17 · 2024: 26 · 2023: 24 · 2022: 14 · 2021: 21 · 2020: 23 · 2019: 20 · 2018: 18 · 2017: 4
FWCI
13.16
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by)
Funders
  • National Institutes of Health (R01AG049402)
  • Italian FFO
  • Canadian Institutes of Health Research
  • Catholic University Intramural Funds
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-beta oligomers, tau oligomers, amyloid precursor protein, long-term potentiation, memory impairment, APP knockout mice, Alzheimer's disease, spatial memory, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Cells, Cultured, Disease Models, Animal, Humans, Memory Disorders, Mice, Inbred C57BL, Neurons, Peptide Fragments, Protein Binding, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Long-Term Potentiation, Mice, Knockout, Protein Multimerization

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