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η-Secretase processing of APP inhibits neuronal activity in the hippocampus

Abstract

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide1. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner1. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo2. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504–505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.

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Figure 1: A novel APP proteolytic processing pathway.
Figure 2: Inhibition of BACE1 results in increased levels of CTF-η and Aη-α.
Figure 3: Aη-α impairs hippocampal LTP.
Figure 4: Aη-α reduces neuronal activity in vivo.

References

  1. Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007)

    CAS  Article  Google Scholar 

  2. Dobrowolska, J. A. et al. CNS amyloid-β, soluble APP-α and -β kinetics during BACE inhibition. J. Neurosci. 34, 8336–8346 (2014)

    Article  Google Scholar 

  3. Haass, C., Koo, E. H., Mellon, A., Hung, A. Y. & Selkoe, D. J. Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357, 500–503 (1992)

    ADS  CAS  Article  Google Scholar 

  4. Estus, S. et al. Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science 255, 726–728 (1992)

    ADS  CAS  Article  Google Scholar 

  5. Haass, C. et al. β-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J. Biol. Chem. 268, 3021–3024 (1993)

    CAS  PubMed  Google Scholar 

  6. Müller, U. et al. Behavioral and anatomical deficits in mice homozygous for a modified β-amyloid precursor protein gene. Cell 79, 755–765 (1994)

    Article  Google Scholar 

  7. Nikolaev, A., McLaughlin, T., O'Leary, D. D. & Tessier-Lavigne, M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457, 981–989 (2009)

    ADS  CAS  Article  Google Scholar 

  8. Jefferson, T. et al. Metalloprotease meprin β generates nontoxic N-terminal amyloid precursor protein fragments in vivo. J. Biol. Chem. 286, 27741–27750 (2011)

    CAS  Article  Google Scholar 

  9. Vella, L. J. & Cappai, R. Identification of a novel amyloid precursor protein processing pathway that generates secreted N-terminal fragments. FASEB J. 26, 2930–2940 (2012)

    CAS  Article  Google Scholar 

  10. Radde, R. et al. Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7, 940–946 (2006)

    CAS  Article  Google Scholar 

  11. Portelius, E. et al. Mass spectrometric characterization of amyloid-β species in the 7PA2 cell model of Alzheimer’s disease. J. Alzheimers Dis. 33, 85–93 (2013)

    CAS  Article  Google Scholar 

  12. Welzel, A. T. et al. Secreted amyloid β-proteins in a cell culture model include N-terminally extended peptides that impair synaptic plasticity. Biochemistry 53, 3908–3921 (2014)

    CAS  Article  Google Scholar 

  13. Higashi, S. & Miyazaki, K. Novel processing of β-amyloid precursor protein catalyzed by membrane type 1 matrix metalloproteinase releases a fragment lacking the inhibitor domain against gelatinase A. Biochemistry 42, 6514–6526 (2003)

    CAS  Article  Google Scholar 

  14. Ahmad, M. et al. Cleavage of amyloid-β precursor protein (APP) by membrane-type matrix metalloproteinases. J. Biochem. 139, 517–526 (2006)

    CAS  Article  Google Scholar 

  15. Folgueras, A. R. et al. Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation. Proc. Natl Acad. Sci. USA 106, 16451–16456 (2009)

    ADS  CAS  Article  Google Scholar 

  16. Zhou, Z. et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl Acad. Sci. USA 97, 4052–4057 (2000)

    ADS  CAS  Article  Google Scholar 

  17. Shi, Y., Kirwan, P. & Livesey, F. J. Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nature Protocols 7, 1836–1846 (2012)

    CAS  Article  Google Scholar 

  18. Moechars, D. et al. Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J. Biol. Chem. 274, 6483–6492 (1999)

    CAS  Article  Google Scholar 

  19. Cai, H. et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nature Neurosci. 4, 233–234 (2001)

    CAS  Article  Google Scholar 

  20. Radde, R. et al. Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7, 940–946 (2006)

    CAS  Article  Google Scholar 

  21. Walsh, D. M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002)

    ADS  CAS  Article  Google Scholar 

  22. Shankar, G. M. et al. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 27, 2866–2875 (2007)

    CAS  Article  Google Scholar 

  23. Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Med. 14, 837–842 (2008)

    CAS  Article  Google Scholar 

  24. Busche, M. A. et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321, 1686–1689 (2008)

    ADS  CAS  Article  Google Scholar 

  25. Busche, M. A. et al. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 109, 8740–8745 (2012)

    ADS  CAS  Article  Google Scholar 

  26. Haass, C. Take five–BACE and the γ-secretase quartet conduct Alzheimer’s amyloid β-peptide generation. EMBO J. 23, 483–488 (2004)

    CAS  Article  Google Scholar 

  27. Sekine-Aizawa, Y. et al. Matrix metalloproteinase (MMP) system in brain: identification and characterization of brain-specific MMP highly expressed in cerebellum. Eur. J. Neurosci. 13, 935–948 (2001)

    CAS  Article  Google Scholar 

  28. Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96–99 (2012)

    ADS  CAS  Article  Google Scholar 

  29. Kuhn, P. H. et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 31, 3157–3168 (2012)

    CAS  Article  Google Scholar 

  30. Zhou, L. et al. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J. Biol. Chem. 287, 25927–25940 (2012)

    CAS  Article  Google Scholar 

  31. Podlisny, M. B. et al. Aggregation of secreted amyloid β-protein into sodium dodecyl sulfate-stable oligomers in cell-culture. J. Biol. Chem. 270, 9564–9570 (1995)

    CAS  Article  Google Scholar 

  32. Kaech, S. & Banker, G. Culturing hippocampal neurons. Nature Protocols 1, 2406–2415 (2006)

    CAS  Article  Google Scholar 

  33. Israel, M. A. et al. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216–220 (2012)

    ADS  CAS  Article  Google Scholar 

  34. Shi, Y., Kirwan, P., Smith, J., Robinson, H. P. & Livesey, F. J. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nature Neurosci. 15, 477–486 (2012)

    CAS  Article  Google Scholar 

  35. Jacobsen, H. et al. Combined treatment with a BACE inhibitor and anti-Ab antibody gantenerumab enhances amyloid reduction in APPLondon mice. J. Neurosci. 34, 11621–11630 (2014)

    CAS  Article  Google Scholar 

  36. Nolan, R. L. & Teller, J. K. Diethylamine extraction of proteins and peptides isolated with a mono-phasic solution of phenol and guanidine isothiocyanate. J. Biochem. Biophys. Methods 68, 127–131 (2006)

    CAS  Article  Google Scholar 

  37. Westmeyer, G. G. et al. Dimerization of β-site β-amyloid precursor protein-cleaving enzyme. J. Biol. Chem. 279, 53205–53212 (2004)

    CAS  Article  Google Scholar 

  38. Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nature Protocols 2, 1896–1906 (2007)

    CAS  Article  Google Scholar 

  39. Scheltema, R. A. et al. The Q Exactive HF, a Benchtop mass spectrometer with a pre-filter, high-performance quadrupole and an ultra-high-field Orbitrap analyzer. Mol. Cell. Proteomics 13, 3698–3708 (2014)

    CAS  Article  Google Scholar 

  40. Olsen, J. V. et al. Higher-energy C-trap dissociation for peptide modification analysis. Nature Methods 4, 709–712 (2007)

    ADS  CAS  Article  Google Scholar 

  41. Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nature Biotechnol. 26, 1367–1372 (2008)

    CAS  Article  Google Scholar 

  42. Cox, J. et al. Andromeda: a peptide search engine integrated into the MaxQuant environment. J. Proteome Res. 10, 1794–1805 (2011)

    ADS  CAS  Article  Google Scholar 

  43. R Development Core Team . R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, http://www.R-project.org/ 2014)

    Google Scholar 

  44. Haass, C. et al. The Swedish mutation causes early-onset Alzheimer’s-disease by β-secretase cleavage within the secretory pathway. Nature Med. 1, 1291–1296 (1995)

    CAS  Article  Google Scholar 

  45. McKhann, G. et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34, 939–944 (1984)

    CAS  Article  Google Scholar 

  46. Lannfelt, L. et al. Amyloid precursor protein mutation causes Alzheimer's disease in a Swedish family. Neurosci. Lett. 168, 254–256 (1994)

    CAS  Article  Google Scholar 

  47. Lannfelt, L. et al. Amyloid β-peptide in cerebrospinal fluid in individuals with the Swedish Alzheimer amyloid precursor protein mutation. Neurosci. Lett. 199, 203–206 (1995)

    CAS  Article  Google Scholar 

  48. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991)

    CAS  Article  Google Scholar 

  49. Mirra, S. S. et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41, 479–486 (1991)

    CAS  Article  Google Scholar 

  50. Hyman, B. T. et al. National Institute on Aging-Alzheime’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 8, 1–13 (2012)

    Article  Google Scholar 

  51. Liao, L. et al. Proteomic characterization of postmortem amyloid plaques isolated by laser capture microdissection. J. Biol. Chem. 279, 37061–37068 (2004)

    CAS  Article  Google Scholar 

  52. Houeland, G. et al. Transgenic mice with chronic NGF deprivation and Alzheimer’s disease-like pathology display hippocampal region-specific impairments in short- and long-term plasticities. J. Neurosci. 30, 13089–13094 (2010)

    CAS  Article  Google Scholar 

  53. Townsend, M., Shankar, G. M., Mehta, T., Walsh, D. M. & Selkoe, D. J. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J. Physiol. (Lond.) 572, 477–492 (2006)

    CAS  Article  Google Scholar 

  54. Stosiek, C., Garaschuk, O., Holthoff, K. & Konnerth, A. In vivo two-photon calcium imaging of neuronal networks. Proc. Natl Acad. Sci. USA 100, 7319–7324 (2003)

    ADS  CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors thank S. Lammich, N. Exner and H. Steiner for critical comments. We thank A. Sülzen, N. Astola, S. Diederich, E. Grießinger and J. Gobbert for technical help. The APPPS1-21 colony was established from a breeding pair provided by M. Jucker. MT1-MMP−/− mouse brains were obtained from Z. Zhou. MT5-MMP−/− mouse brains were obtained from I. Farinas. We thank H. Jacobsen for the BACE1 inhibitor RO5508887. This work was supported by the European Research Council under the European Union’s Seventh Framework Program (FP7/2007–2013)/ERC grant agreement no. 321366-Amyloid (advanced grant to C.H.). The work of D.R.T. was supported by AFI (grant 13803). The research leading to these results has received funding (F.M. and D.H.) from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. 318987 [TOPAG]. We thank J. Cox and M. Mann for critical discussions and the mass spectrometry infrastructure. We also acknowledge support by grants from Deutsche Forschungsgemeinschaft (MU 1457/9-1, 9-2 to U.M.) and the ERA-Net Neuron (01EW1305A to U.M.). Further support came from the ATIP/AVENIR program (Centre national de la recherche scientifique, CNRS) to H.M.; the French Fondation pour la Coopération Scientifique – Plan Alzheimer (Senior Innovative Grant 2010) to M.C. and H.M., and the French Government (National Research Agency, ANR) through the “Investments for the Future” LABEX SIGNALIFE: program reference ANR-11-LABX-0028-01 to S.K. M.A.B. was supported by the Langmatz Stiftung. F.J.L. is a Wellcome Trust Investigator. In vivo BACE1 inhibition experiments with APP transgenic mice were performed together with reMYND (Bio-Incubator, 3001 Leuven-Heverlee, Belgium).

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Authors and Affiliations

Authors

Contributions

M.W. and C.H. designed the study and interpreted the results. M.W. generated all biochemical data together with H.H., V.M., B.N. and C.G. S.T., supported by A.W.-W., provided primary neuronal cultures, performed and analysed immunohistological stainings, and together with A.D. performed LCM. D.R.T. provided and analysed human brain sections. M.T.H. provided CSF samples. U.M. provided APP-knockout mice. E.K. produced new monoclonal antibodies. D.H. and F.M. designed and conducted mass spectrometry and data analysis. L.D.B.E., S.M. and F.J.L. carried out BACE1 inhibition of human neurons. H.M. together with M.C. and S.K. performed all electrophysiological recordings (LTP) in vitro and analysis in relation to application of peptides. S.V.O. and J.H. performed all electrophysiological recordings (LTP) in vitro in relation to the BACE1 inhibitor tests. M.A.B and A.K. performed all Ca2+-imaging experiments in vivo and analysis. M.W. and C.H. wrote the manuscript with input from the other authors. Correspondence and requests for materials should be addressed to M.W. and C.H.

Corresponding authors

Correspondence to Michael Willem or Christian Haass.

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M.W. and C.H. have filed a patent for analytical and therapeutic use of Aη peptides.

Extended data figures and tables

Extended Data Figure 1 Schematic presentation of the η-secretase processing pathway.

Schematic representation of the η-secretase pathway (left) as compared to the amyloidogenic pathway (right). Antibodies used in this study are indicated.

Extended Data Figure 2 η-Secretase cleavage at Met505 of APP695.

MMP proteins can cleave human APP695 at the indicated position (arrow) between amino acids N504 and M505 in the N-terminal domain. The epitope for the neo-epitope-specific antibody 10A8 is indicated (grey line). sAPP-η was specifically detected in diethylamine (DEA; 0.2% diethylamine in 50 mM NaCl, pH 10) extracts of P10 wild-type mouse brain using antibody 10A8, but was absent in APP-knockout brains. Of note, antibody 10A8 failed to detect sAPP-α/β, confirming its selectivity for the η-cleavage site.

Extended Data Figure 3 Mass spectrometry analysis of Aη peptides.

a, b, After removal of sAPP-α from conditioned media of CHO 7PA2 cells using appropriate centricon filters, the flow-through was used to isolate Aη peptides by immunoprecipitation. Synthetic peptides (1 ng per lane) were loaded to indicate the respective sizes of Aη-α and Aη-β. Aη peptides were captured with antibodies 9476M and 9478D directed against the putative N-terminal epitopes (Supplementary Table 1), 2E9 against a middle domain of Aη and 2D8 (which also immunoprecipitates amyloid-β). 2D8 detection (a) revealed that all antibodies captured peptides positive for the N-terminal part of the amyloid-β domain in a molecular mass range of synthetic Aη-α between 12 and 16 kDa. The same samples analysed with 2E9 (b) confirmed the presence of Aη in all samples, with the lowest levels when precipitated with 9476M. Note that unlike 2D8 antibody, 2E9 allows the additional detection of Aη-β. (Asterisks denote IgG.) c, A heat map of peptides identified after analytic proteolysis by mass spectrometry analysis, with 7PA2 supernatants immunoprecipitated with 2D8, 2E9, 9476M and 9478D antibodies. Arrows indicate peptides that start exactly with the amino acid sequence C-terminal of the respective cleavage sites of the η-secretase, β-secretase or α-secretase site. Chy, chymotrypsin; LysC, protease LysC; tryp, trypsin.

Extended Data Figure 4 MT5-MMP displays η-secretase activity in brain.

ac, MT1-MMP−/− and MT5-MMP−/− (also known as Mmp14−/− and Mmp24−/−, respectively) mice were analysed for changes in η-secretase activity. Membrane and soluble proteins from P10 mouse brains were analysed. a, In RIPA lysates, no changes in APP and BACE1 levels were detected in knockout brains. MT1- and MT5-MMP were selectively knocked out as shown by the lack of signals in western blots. Calnexin served as a loading control. Soluble Aη levels, detected by antibodies 9478D and M3.2 (Aη-α) were unchanged in MT1-MMP−/− mouse brains (b), but reduced in MT5-MMP−/− mouse brains (c). Total levels of secreted APP (22C11), sAPP-α or sAPP-β were unchanged (b, c).

Extended Data Figure 5 Accumulation of CTF-η in dystrophic neurites.

a, Immunohistological stainings of cortical sections of 6-month-old APPPS1-21 transgenic mice (n = 3) revealed 6E10-positive amyloid-β plaque cores (encircled) surrounded by dystrophic neurites positive for 2E9 (white arrowheads, top) and 9476M (white arrowheads, middle). Y188 (bottom panel) staining co-localized with 2E9-positive signal (yellow arrowheads, bottom). Nuclei were counterstained with DAPI. Scale bar, 10 μm. b, Accumulation of CTF-η fragment in dystrophic neurites of 14-month and 24-month-old APPPS1-21 mice. Western blot analysis of material obtained by LCM of APPPS1-21 brain sections (n = 5) bearing thioflavin-S-positive amyloid-β plaque core (P) and the surrounding amyloid-β plaque halo (H). As a control (C), brain areas devoid of plaques were used. While amyloid-β was readily detected by antibody 2D8 in lysates containing plaque-enriched material and halo regions (fractions P and H; bottom), CTF-η was selectively detected in the lysates prepared from the region enriched in dystrophic neurites (H; top), but not detected in plaque or control regions (P or C). As expected, CTF-β/α species are also enriched in dystrophic neurites (H).

Extended Data Figure 6 Dystrophic neurites in AD brains are positive for Aη-epitope antibodies.

af, Immunohistochemistry with 22C11 (a, b), 9478D (c, d) and 9476M (e, f) antibodies in the human hippocampus (CA1-subiculum region) of a control case (a, c, e) and an AD case (b, d, f). Immuno-positive signals were observed with 22C11 (a), 9478D (c) and 9476M (e) antibodies in the somata and neuropils of a normal and AD brain. In AD brains, these antibodies decorate dystrophic neurites (b, d, f, denoted by arrowheads). Scale bar, 30 μm. NP, neuritic plaque.

Extended Data Figure 7 Increased Aη levels after acute treatment with a BACE1 inhibitor.

a, In membrane lysates of brains obtained from animals treated with BACE1 inhibitor (BI, 100 mg kg−1 SCH1682496), an increase in CTF-η was observed, which was paralleled by a strong reduction of CTF-β, while CTF-α was unchanged. APP-FL and BACE1 signals remained unchanged (asterisk indicates background band). Calnexin served as a loading control. b, In the soluble fraction, BACE1 inhibition resulted in enhanced Aη-α levels and reduced sAPP-β levels, indicating efficient BACE1 inhibition. c, Production of Aη-α species, which was detected by antibody M3.2, revealed a 95.4% increase after BACE1 inhibition. n = 3; P < 0.01, Student’s t-test.

Extended Data Figure 8 Aη-α and Aη-β derived from CHO cells did not influence baseline activity at the hippocampal CA3–CA1 synapse.

Soluble Aη-α and Aη-β peptides were expressed in CHO cells and collected in OPTIMEM medium. a, b, SEC fractions containing Aη were diluted (1:15) in ACSF for the treatment of hippocampal slices and LTP measurements. Aη-α or Αη-β SEC fractions were perfused over mouse hippocampal slices after obtaining a 15-min stable baseline of a fEPSP at the CA3–CA1 synapse. The baseline remained unchanged for another 15 min when slices were incubated with CHO-cell-derived recombinant Aη-α (a) or Aη-β (b).

Extended Data Figure 9 AβS26C dimers and synthetic Aη-α impair hippocampal LTP.

a, In line with previous findings23, AβS26C cross-linked dimers (containing cysteine instead of serine at residue 26; 100 nM final; JPT Peptide Technologies; diluted in 25 ml re-circulating ACSF) reduced LTP as compared to interleaved control LTP recordings in 25 ml re-circulating ACSF. b, Illustrated is the average LTP magnitude (at 45–60 min after LTP induction) normalized to pre-LTP baseline values (100%) in untreated and treated conditions (***P < 0.001; Student’s t-test). c, Treatment with synthetic Aη-α (100 nM final; Peptide Speciality Laboratories; diluted in 25 ml re-circulating ACSF) reduced LTP as compared to interleaved control LTP recordings in 25 ml re-circulating ACSF. d, Illustrated is the average LTP magnitude (at 45–60 min post-LTP induction) normalized to pre-LTP baseline values (100%) in treated and untreated conditions (*P < 0.05; Student’s t-test).

Extended Data Figure 10 Aη-α decreases the frequencies of neuronal calcium transients in vivo.

af, Histograms showing in each panel the corresponding distributions of calcium transients before (control) and during subsequent exposure of Aη peptides (b, c, e, f) and controls (a, d).

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Willem, M., Tahirovic, S., Busche, M. et al. η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526, 443–447 (2015). https://doi.org/10.1038/nature14864

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