[go: up one dir, main page]
Skip to main content

Advertisement

SpringerLink
Log in

Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer’s disease

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Progressive accumulation of Alzheimer’s disease-related pathology is associated with cognitive dysfunction. Differences in cognitive reserve may contribute to individual differences in cognitive function in the presence of comparable neuropathology. The protective effects of cognitive reserve could contribute differentially in early versus late stages of the disease. We investigated presynaptic proteins as measures of brain reserve (a subset of total cognitive reserve), and used Braak staging to estimate the progression of Alzheimer’s disease. Antemortem evaluations of cognitive function, postmortem assessments of pathologic indices, and presynaptic protein analyses, including the complexins I and II as respective measures of inhibitory and excitatory terminal function, were assayed in multiple key brain regions in 418 deceased participants from a community study. After covarying for demographic variables, pathologic indices, and overall synapse density, lower brain complexin-I and -II levels contributed to cognitive dysfunction (P < 0.01). Each complexin appeared to be dysregulated at a different Braak stage. Inhibitory complexin-I explained 14.4% of the variance in global cognition in Braak 0–II, while excitatory complexin-II explained 7.3% of the variance in Braak V–VI. Unlike other presynaptic proteins, complexins did not colocalize with pathologic tau within neuritic plaques, suggesting that these functional components of the synaptic machinery are cleared early from dystrophic neurites. Moreover, complexin levels showed distinct patterns of change related to memory challenges in a rat model, supporting the functional specificity of these proteins. The present results suggest that disruption of inhibitory synaptic terminals may trigger early cognitive impairment, while excitatory terminal disruption may contribute relatively more to later cognitive impairment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  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. doi:10.1016/j.neuron.2012.03.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Barakauskas VE, Beasley CL, Barr AM, Ypsilanti AR, Li H-Y, Thornton AE, Wong H, Rosokilja G, Mann JJ, Mancevski B, Jakovski Z, Davceva N, Ilievski B, Dwork AJ, Falkai P, Honer WG (2010) A novel mechanism and treatment target for presynaptic abnormalities in specific striatal regions in schizophrenia. Neuropsychopharmacol 35:1226–1238. doi:10.1038/npp.2009.228

    Article  CAS  Google Scholar 

  3. Begemann M, Grube S, Papiol S, Malzahn D, Krampe H, Ribbe K, Friedrichs H, Radyushkin KA, El-Kordi A, Benseler F, Hannke K, Sperling S, Schwerdtfeger D, Thanhäuser I, Gerchen MF, Ghorbani M, Gutwinski S, Hilmes C, Leppert R, Ronnenberg A, Sowislo J, Stawicki S, Stödtke M, Szuszies C, Reim K, Riggert J, Eckstein F, Falkai P, Bickeböller H, Nave K-A, Brose N, Ehrenreich H (2010) Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. Arch Gen Psychiatry 67:879–888. doi:10.1001/archgenpsychiatry.2010.107

    Article  CAS  PubMed  Google Scholar 

  4. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, Wilson RS (2006) Neuropathology of older persons without cognitive impairment from two community-based studies. Neurol 66:1837–1844. doi:10.1212/01.wnl.0000219668.47116.e6

    Article  CAS  Google Scholar 

  5. Bennett DA, Schneider JA, Buchman AS, Mendes de Leon C, Bienias JL, Wilson RS (2005) The Rush Memory and Aging Project: study design and baseline characteristics of the study cohort. Neuroepidemiol 25:163–175. doi:10.1159/000087446

    Article  Google Scholar 

  6. Bennett DA, Wilson RS, Arvanitakis Z, Boyle PA, de Toledo-Morrell L, Schneider JA (2013) Selected findings from the Religious Orders Study and Rush Memory and Aging Project. J Alzheimers Dis 33(Suppl 1):S397–S403. doi:10.3233/JAD-2012-129007

    PubMed  PubMed Central  Google Scholar 

  7. Bossers K, Wirz KTS, Meerhoff GF, Essing AHW, van Dongen JW, Houba P, Kruse CG, Verhaagen J, Swaab DF (2010) Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer’s disease. Brain 133:3699–3723. doi:10.1093/brain/awq258

    Article  PubMed  Google Scholar 

  8. Boyle PA, Wilson RS, Aggarwal NT, Tang Y, Bennett DA (2006) Mild cognitive impairment: risk of Alzheimer disease and rate of cognitive decline. Neurol 67:441–445. doi:10.1212/01.wnl.0000228244.10416.20

    Article  CAS  Google Scholar 

  9. Boyle PA, Wilson RS, Yu L, Barr AM, Honer WG, Schneider JA, Bennett DA (2013) Much of late life cognitive decline is not due to common neurodegenerative pathologies. Ann Neurol 74:478–489. doi:10.1002/ana.23964

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Braak H, Del Tredici K (2015) The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease. Brain 138:2814–2833. doi:10.1093/brain/awv236

    Article  PubMed  Google Scholar 

  12. Brion JP, Couck AM, Bruce M, Anderton B, Flament-Durand J (1991) Synaptophysin and chromogranin A immunoreactivities in senile plaques of Alzheimer’s disease. Brain Res 539:143–150

    Article  CAS  PubMed  Google Scholar 

  13. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold K-H, Haass C, Staufenbiel M, Konnerth A, Garaschuk O (2008) Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321:1686–1689. doi:10.1126/science.1162844

    Article  CAS  PubMed  Google Scholar 

  14. Costes SV, Daelemans D, Cho EH, Dobbin Z, Pavlakis G, Lockett S (2004) Automatic and quantitative measurement of protein–protein colocalization in live cells. Biophys J 86:3993–4003. doi:10.1529/biophysj.103.038422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, Arnold SE, Attems J, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Gearing M, Grinberg LT, Hof PR, Hyman BT, Jellinger K, Jicha GA, Kovacs GG, Knopman DS, Kofler J, Kukull WA, Mackenzie IR, Masliah E, McKee A, Montine TJ, Murray ME, Neltner JH, Santa-Maria I, Seeley WW, Serrano-Pozo A, Shelanski ML, Stein T, Takao M, Thal DR, Toledo JB, Troncoso JC, Vonsattel JP, White CL, Wisniewski T, Woltjer RL, Yamada M, Nelson PT (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128:755–766. doi:10.1007/s00401-014-1349-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cumbo E, Ligori LD (2010) Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease. Epilepsy Behav 17:461–466. doi:10.1016/j.yebeh.2010.01.015

    Article  PubMed  Google Scholar 

  17. Davis S, Rodger J, Hicks A, Mallet J, Laroche S (1996) Brain structure and task-specific increase in expression of the gene encoding syntaxin 1B during learning in the rat: a potential molecular marker for learning-induced synaptic plasticity in neural networks. Eur J Neurosci 8:2068–2074

    Article  CAS  PubMed  Google Scholar 

  18. Gray EG, Whittaker VP (1962) The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. J Anat 96:79–88

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hass J, Walton E, Kirsten H, Turner J, Wolthusen R, Roessner V, Sponheim SR, Holt D, Gollub R, Calhoun VD, Ehrlich S (2014) Complexin2 modulates working memory-related neural activity in patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci 265:137–145. doi:10.1007/s00406-014-0550-4

    Article  PubMed  PubMed Central  Google Scholar 

  20. Honer WG, Barr AM, Sawada K, Thornton AE, Morris MC, Leurgans SE, Schneider JA, Bennett DA (2012) Cognitive reserve, presynaptic proteins and dementia in the elderly. Transl Psychiatry 2:e114. doi:10.1038/tp.2012.38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Honer WG, Hu L, Davies P (1993) Human synaptic proteins with a heterogeneous distribution in cerebellum and visual cortex. Brain Res 609:9–20

    Article  CAS  PubMed  Google Scholar 

  22. Ihaka R, Gentleman R (1996) R: a language for data analysis and graphics. J Comput Graph Stat 5:299–314

    Google Scholar 

  23. Koliatsos VE, Kecojevic A, Troncoso JC, Gastard MC, Bennett DA, Schneider JA (2006) Early involvement of small inhibitory cortical interneurons in Alzheimer’s disease. Acta Neuropathol 112:147–162. doi:10.1007/s00401-006-0068-6

    Article  CAS  PubMed  Google Scholar 

  24. Lewis J, Dickson DW (2015) Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol 131:27–48. doi:10.1007/s00401-015-1507-z

    Article  PubMed  Google Scholar 

  25. Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H (2016) Implications of GABAergic neurotransmission in Alzheimer’s disease. Front Aging Neurosci 8:31. doi:10.3389/fnagi.2016.00031

    PubMed  PubMed Central  Google Scholar 

  26. Luo J, Lee SH, VandeVrede L, Qin Z, Ben Aissa M, Larson J, Teich AF, Arancio O, D’Souza Y, Elharram A, Koster K, Tai LM, LaDu MJ, Bennett BM, Thatcher GRJ (2016) A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer’s disease. Mol Neurodegener 11:35. doi:10.1186/s13024-016-0103-6

    Article  PubMed  PubMed Central  Google Scholar 

  27. Luo J, Lee SH, VandeVrede L, Qin Z, Piyankarage S, Tavassoli E, Asghodom RT, Ben Aissa M, Fà M, Arancio O, Yue L, Pepperberg DR, Thatcher GRJ (2015) Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia. BMC Neurosci 16:67. doi:10.1186/s12868-015-0208-9

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B (2004) The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci 101:9861–9866. doi:10.1073/pnas.0308208101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Masliah E, Honer WG, Mallory M, Voigt M, Kushner P, Hansen L, Terry R (1994) Topographical distribution of synaptic-associated proteins in the neuritic plaques of Alzheimer’s disease hippocampus. Acta Neuropathol 87:135–142

    Article  CAS  PubMed  Google Scholar 

  30. Matveeva EA, Vanaman TC, Whiteheart SW, Slevin JT (2008) Levetiracetam prevents kindling-induced asymmetric accumulation of hippocampal 7S SNARE complexes. Epilepsia 49:1749–1758. doi:10.1111/j.1528-1167.2008.01687.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Minger SL, Honer WG, Esiri MM, McDonald B, Keene J, Nicoll JA, Carter J, Hope T, Francis PT (2001) Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer disease. J Neuropathol Exp Neurol 60:929–936

    Article  CAS  PubMed  Google Scholar 

  32. Mirra SS, Hart MN, Terry RD (1993) Making the diagnosis of Alzheimer’s disease. A primer for practicing pathologists. Arch Pathol Lab Med 117:132–144

    CAS  PubMed  Google Scholar 

  33. National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer”s Disease (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer“s disease. Neurobiol Aging 18(4S):S1–S2

    Google Scholar 

  34. Neuropathology Group, Medical Research Council Cognitive Function and Aging Study (2001) Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet 357:169–175

    Article  Google Scholar 

  35. Palop JJ, Mucke L (2009) Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol 66:435–440. doi:10.1001/archneurol.2009.15

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ramos-Miguel A, Hercher C, Beasley CL, Barr AM, Bayer TA, Falkai P, Leurgans SE, Schneider JA, Bennett DA, Honer WG (2015) Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample. Mol Neurodegener 10:65. doi:10.1186/s13024-015-0061-4

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ramos-Miguel A, Honer WG, Boyda HN, Sawada K, Beasley CL, Procyshyn RM, Barr AM (2015) Exercise prevents downregulation of hippocampal presynaptic proteins following olanzapine-elicited metabolic dysregulation in rats: Distinct roles of inhibitory and excitatory terminals. Neurosci 301:298–311. doi:10.1016/j.neuroscience.2015.06.022

    Article  CAS  Google Scholar 

  38. Riley KP, Snowdon DA, Markesbery WR (2002) Alzheimer’s neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol 51:567–577. doi:10.1002/ana.10161

    Article  PubMed  Google Scholar 

  39. Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu G-Q, Palop JJ, Mucke L (2012) Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci 109:E2895–E2903. doi:10.1073/pnas.1121081109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Saura CA, Parra-Damas A, Enriquez-Barreto L (2015) Gene expression parallels synaptic excitability and plasticity changes in Alzheimer’s disease. Front Cell Neurosci 9:1567. doi:10.1038/npp.2011.107

    Article  Google Scholar 

  41. Sawada K, Barr AM, Nakamura M, Arima K, Young CE, Dwork AJ, Falkai P, Phillips AG, Honer WG (2005) Hippocampal complexin proteins and cognitive dysfunction in schizophrenia. Arch Gen Psychiatry 62:263–272. doi:10.1001/archpsyc.62.3.263

    Article  CAS  PubMed  Google Scholar 

  42. Sawada K, Young CE, Barr AM, Longworth K, Takahashi S, Arango V, Mann JJ, Dwork AJ, Falkai P, Phillips AG, Honer WG (2002) Altered immunoreactivity of complexin protein in prefrontal cortex in severe mental illness. Mol Psychiatry 7:484–492. doi:10.1038/sj.mp.4000978

    Article  CAS  PubMed  Google Scholar 

  43. Schneider JA, Arvanitakis Z, Bang W, Bennett DA (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69:2197–2204. doi:10.1212/01.wnl.0000271090.28148.24

    Article  PubMed  Google Scholar 

  44. Serrano-Pozo A, Qian J, Muzikansky A, Monsell SE, Montine TJ, Frosch MP, Betensky RA, Hyman BT (2016) Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer disease continuum. J Neuropathol Exp Neurol 75:516–526. doi:10.1093/jnen/nlw026

    Article  PubMed  Google Scholar 

  45. Solodkin A, Veldhuizen SD, Van Hoesen GW (1996) Contingent vulnerability of entorhinal parvalbumin-containing neurons in Alzheimer’s disease. J Neurosci 16:3311–3321

    CAS  PubMed  Google Scholar 

  46. Spires-Jones TL, Hyman BT (2014) The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82:756–771. doi:10.1016/j.neuron.2014.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Stargardt A, Swaab DF, Bossers K (2015) The storm before the quiet: neuronal hyperactivity and Abeta in the presymptomatic stages of Alzheimer’s disease. Neurobiol Aging 36:1–11. doi:10.1016/j.neurobiolaging.2014.08.014

    Article  CAS  PubMed  Google Scholar 

  48. Stern Y (2009) Cognitive reserve. Neuropsychologia 47:2015–2028. doi:10.1016/j.neuropsychologia.2009.03.004

    Article  PubMed  PubMed Central  Google Scholar 

  49. Takahashi S, Ujihara H, Huang GZ, Yagyu KI, Sanbo M, Kaba H, Yagi T (1999) Reduced hippocampal LTP in mice lacking a presynaptic protein: complexin II. Eur J Neurosci 11:2359–2366

    Article  CAS  PubMed  Google Scholar 

  50. Takahashi S, Yamamoto H, Matsuda Z, Ogawa M, Yagyu K, Taniguchi T, Miyata T, Kaba H, Higuchi T, Okutani F (1995) Identification of two highly homologous presynaptic proteins distinctly localized at the dendritic and somatic synapses. FEBS Lett 368:455–460

    Article  CAS  PubMed  Google Scholar 

  51. Tong LM, Yoon SY, Andrews-Zwilling Y, Yang A, Lin V, Lei H, Huang Y (2016) Enhancing GABA signaling during middle adulthood prevents age-dependent GABAergic interneuron decline and learning and memory deficits in ApoE4 Mice. J Neurosci 36:2316–2322. doi:10.1523/JNEUROSCI.3815-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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 Neurol 70:1158–1166. doi:10.1001/jamaneurol.2013.136

    Article  PubMed  PubMed Central  Google Scholar 

  53. Wakabayashi K, Honer WG, Masliah E (1994) Synapse alterations in the hippocampal-entorhinal formation in Alzheimer’s disease with and without Lewy body disease. Brain Res 667:24–32

    Article  CAS  PubMed  Google Scholar 

  54. Wang D, Munoz DG (1995) Qualitative and quantitative differences in senile plaque dystrophic neurites of Alzheimer’s disease and normal aged brain. J Neuropathol Exp Neurol 54:548–556

    Article  CAS  PubMed  Google Scholar 

  55. Winship C, Mare RD (1984) Regression models with ordinal variables. Am Sociol Rev 49:512–525

    Article  Google Scholar 

  56. Yamada M, Saisu H, Ishizuka T, Takahashi H, Abe T (1999) Immunohistochemical distribution of the two isoforms of synaphin/complexin involved in neurotransmitter release: localization at the distinct central nervous system regions and synaptic types. Neurosci 93:7–18

    Article  CAS  Google Scholar 

  57. Young CE, Arima K, Xie J, Hu L, Beach TG, Falkai P, Honer WG (1998) SNAP-25 deficit and hippocampal connectivity in schizophrenia. Cereb Cortex 8:261–268

    Article  CAS  PubMed  Google Scholar 

  58. Yu L, Boyle PA, Segawa E, Leurgans S, Schneider JA, Wilson RS, Bennett DA (2015) Residual decline in cognition after adjustment for common neuropathologic conditions. Neuropsychol 29:335–343. doi:10.1037/neu0000159

    Article  Google Scholar 

Download references

Acknowledgements

We thank Hong-Ying Li and Jenny Yang for their skillful technical assistance. The present work was financed with Grants from the Canadian Institutes of Health Research (MT-14037, MOP-81112). The Memory and Aging Project represents a collaborative, multidisciplinary and prospective research supported by the National Institute on Aging (Grants R01AG17917, R01AG42210). Dr. W.G. Honer was supported by the Jack Bell Chair in Schizophrenia.

Author information

Authors and Affiliations

  1. BC Mental Health and Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada

    Alfredo Ramos-Miguel, Andrea A. Jones, Allen E. Thornton, Alasdair M. Barr & William G. Honer

  2. Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada

    Alfredo Ramos-Miguel, Andrea A. Jones & William G. Honer

  3. Kochi Prefectural Aki General Hospital, 3-33 Hoheicho, Kochi, 784-0027, Japan

    Ken Sawada

  4. Department of Psychology, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada

    Allen E. Thornton

  5. Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada

    Alasdair M. Barr

  6. Rush Alzheimer’s Disease Center, Rush University Medical Center, 600 S Paulina Street, Chicago, IL, 60612, USA

    Sue E. Leurgans, Julie A. Schneider & David A. Bennett

Authors
  1. Alfredo Ramos-Miguel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ken Sawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea A. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Allen E. Thornton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alasdair M. Barr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sue E. Leurgans
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julie A. Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David A. Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William G. Honer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William G. Honer.

Ethics declarations

Conflict of interest

Dr. W.G. Honer has received consulting fees or sat on paid advisory boards for: In Silico, Lundbeck/Otsuka, Eli Lilly, and Roche. Dr. A.M. Barr is on the advisory board or received consulting fees from Roche Canada, and received educational grant support from BMS Canada. The Organizations cited above had no role in (and, therefore, did not influence) the design of this study, the interpretation of results, and/or preparation of the manuscript. All other authors have no financial interest on the reported data and declare that no competing interests exist.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ramos-Miguel, A., Sawada, K., Jones, A.A. et al. Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer’s disease. Acta Neuropathol 133, 395–407 (2017). https://doi.org/10.1007/s00401-016-1647-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-016-1647-9

Keywords

Search

Navigation