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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2015

Open Access 01-12-2015 | Research article

Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample

Authors: Alfredo Ramos-Miguel, Christa Hercher, Clare L. Beasley, Alasdair M. Barr, Thomas A. Bayer, Peter Falkai, Sue E. Leurgans, Julie A. Schneider, David A. Bennett, William G. Honer

Published in: Molecular Neurodegeneration | Issue 1/2015

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Abstract

Background

Presynaptic terminals contribute to cognitive reserve, balancing the effects of age-related pathologies on cognitive function in the elderly. The presynaptic protein Munc18-1, alternatively spliced into long (M18L) or short (M18S) isoforms, is a critical modulator of neurotransmission. While subtle alterations in Munc18-1 have been shown to cause severe neuropsychiatric disorders with cognitive impairment, little information is known regarding the specific roles of Munc18-1 splice variants. We first investigated functional and anatomical features evidencing the divergent roles of M18L and M18S, and then evaluated their contribution to the full range of age-related cognitive impairment in the dorsolateral prefrontal cortex of a large sample of participants from a community-based aging study, including subjects with no-(NCI, n = 90), or mild-(MCI, n = 86) cognitive impairment, or with clinical dementia (n = 132). Finally, we used APP23 mutant mice to study the association between M18L/S and the time-dependent accumulation of common Alzheimer’s disease pathology.

Results

Using isoform-specific antibodies, M18L was localized to the synaptosomal fraction, with a distribution matching lipid raft microdomains. M18S was found widely across cytosolic and synaptosomal compartments. Immunocytochemical studies identified M18L in perisomatic, GABAergic terminals, while M18S was broadly distributed in GABAergic and glutamatergic terminals. Using regression models taking into account multiple age-related pathologies, age, education and sex, global cognitive function was associated with the level of M18L (p = 0.006) but not M18S (p = 0.88). Mean M18L in dementia cases was 51 % lower than in NCI cases (p < 0.001), and each unit of M18L was associated with a lower likelihood of dementia (odds ratio = 0.68, 95 % confidence interval = 0.50–0.90, p = 0.008). In contrast, M18S balanced across clinical and pathologically diagnosed groups. M18L loss may not be caused by age-related amyloid pathology, since APP23 mice (12- and 22-months of age) had unchanged cortical levels of M18L/S compared with wild-type animals.

Conclusions

M18L was localized to presynaptic inhibitory terminals, and was associated with cognitive function and protection from dementia in an elderly, community-based cohort. Lower M18L in inhibitory presynaptic terminals may be an early, independent contributor to cognitive decline.
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Literature
1.
Satz P. Brain reserve capacity on symptom onset after brain injury: A formulation and review of evidence for threshold theory. Neuropsychology. 1993;7:273–95.CrossRef
2.
Stern Y. What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc. 2002;8:448–60.CrossRefPubMed
3.
Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P. Clinical, pathological, and neurochemical changes in dementia: A subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol. 1988;23:138–44.CrossRefPubMed
4.
White L, Small BJ, Petrovitch H, Ross GW, Masaki K, Abbott RD, et al. Recent clinical-pathologic research on the causes of dementia in late life: update from the Honolulu-Asia Aging Study. J Geriatr Psychiatry Neurol. 2005;18:224–7.CrossRefPubMed
5.
Bryne C, Matthews FE, Xuereb JH, Broome JC, McKenzie J, Rossi M, et al. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet. 2001;357:169–75.CrossRef
6.
Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277:813–7.CrossRefPubMed
7.
Bennett DA, Schneider JA, Buchman AS, Barnes LL, Boyle PA, Wilson RS. Overview and findings from the Rush Memory and Aging Project. Curr Alzheimer Res. 2012;9:646–63.PubMedCentralCrossRefPubMed
8.
Lassmann H, Weiler R, Fischer P, Bancher C, Jellinger K, Floor E, et al. Synaptic pathology in Alzheimer’s disease: immunological data for markers of synaptic and large dense-core vesicles. Neuroscience. 1992;46:1–8.CrossRefPubMed
9.
Honer WG, Dickson DW, Gleeson J, Davies P. Regional synaptic pathology in Alzheimer’s disease. Neurobiol Aging. 1992;13:375–82.CrossRefPubMed
10.
Masliah E, Hansen L, Albright T, Mallory M, Terry RD. Immunoelectron microscopic study of synaptic pathology in Alzheimer’s disease. Acta Neuropathol. 1991;81:428–33.CrossRefPubMed
11.
Lassmann H, Fischer P, Jellinger K. Synaptic pathology of Alzheimer’s disease. Ann N Y Acad Sci. 1993;695:59–64.CrossRefPubMed
12.
Honer WG. Pathology of presynaptic proteins in Alzheimer’s disease: more than simple loss of terminals. Neurobiol Aging. 2003;24:1047–62.CrossRefPubMed
13.
Honer WG, Barr AM, Sawada K, Thornton AE, Morris MC, Leurgans SE, et al. Cognitive reserve, presynaptic proteins and dementia in the elderly. Transl Psychiatry. 2012;2:e114.PubMedCentralCrossRefPubMed
14.
Boyle PA, Wilson RS, Yu L, Barr AM, Honer WG, Schneider JA, et al. Much of late life cognitive decline is not due to common neurodegenerative pathologies. Ann Neurol. 2013;74:478–89.CrossRefPubMed
15.
Söllner T, Bennett MK, Whiteheart SW, Scheller RH, Rothman JE. A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell. 1993;75:409–18.CrossRefPubMed
16.
Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA. The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol. 2009;66:200–8.PubMedCentralCrossRefPubMed
17.
Minger SL, Honer WG, Esiri MM, McDonald B, Keene J, Nicoll JA, et al. Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer disease. J Neuropathol Exp Neurol. 2001;60:929–36.PubMed
18.
Harrington CR, Wischik CM, Honer W, Jakes RG, McGee M, Paykel ES, et al. Staging of Cytoskeletal and β-Amyloid Changes in Human Isocortex Reveals Biphasic Synaptic Protein Response during Progression of Alzheimer’s Disease. Am J Pathol. 2000;157:623–36.PubMedCentralCrossRefPubMed
19.
Berchtold NC, Sabbagh MN, Beach TG, Kim RC, Cribbs DH, Cotman CW. Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer’s disease. Neurobiol Aging. 2014;35:1961–72.PubMedCentralCrossRefPubMed
20.
Nakata Y, Yasuda T, Fukaya M, Yamamori S, Itakura M, Nihira T, et al. Accumulation of α-synuclein triggered by presynaptic dysfunction. J Neurosci. 2012;32:17186–96.CrossRefPubMed
21.
Sharma M, Burre J, Sudhof TC. Proteasome Inhibition Alleviates SNARE-Dependent Neurodegeneration. Sci Transl Med. 2012;4:147ra113.CrossRefPubMed
22.
23.
Toonen RFG, Verhage M. Munc18-1 in secretion: lonely Munc joins SNARE team and takes control. Trends Neurosci. 2007;30:564–72.CrossRefPubMed
24.
Südhof TC. Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron. 2013;80:675–90.CrossRefPubMed
25.
Hata Y, Slaughter CA, Südhof TC. Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature. 1993;366:347–51.CrossRefPubMed
26.
Hosono R, Hekimi S, Kamiya Y, Sassa T, Murakami S, Nishiwaki K, et al. The unc-18 gene encodes a novel protein affecting the kinetics of acetylcholine metabolism in the nematode Caenorhabditis elegans. J Neurochem. 1992;58:1517–25.CrossRefPubMed
27.
28.
Rizo J, Südhof TC. The membrane fusion enigma: SNAREs, Sec1/Munc18 proteins, and their accomplices--guilty as charged? Annu Rev Cell Dev Biol. 2012;28:279–308.CrossRefPubMed
29.
Han GA, Malintan NT, Collins BM, Meunier FA, Sugita S. Munc18-1 as a key regulator of neurosecretion. J Neurochem. 2010;115:1–10.CrossRefPubMed
30.
Verhage M, Maia AS, Plomp JJ, Brussaard AB, Heeroma JH, Vermeer H, et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science. 2000;287:864–9.CrossRefPubMed
31.
Swanson DA, Steel JM, Valle D. Identification and characterization of the human ortholog of rat STXBP1, a protein implicated in vesicle trafficking and neurotransmitter release. Genomics. 1998;48:373–6.CrossRefPubMed
32.
Garcia EP, McPherson PS, Chilcote TJ, Takei K, De Camilli P. rbSec1A and B colocalize with syntaxin 1 and SNAP-25 throughout the axon, but are not in a stable complex with syntaxin. J Cell Biol. 1995;129:105–10.CrossRefPubMed
33.
Cijsouw T, Weber JP, Broeke JH, Broek JAC, Schut D, Kroon T, et al. Munc18-1 redistributes in nerve terminals in an activity- and PKC-dependent manner. J Cell Biol. 2014;204:759–75.PubMedCentralCrossRefPubMed
34.
35.
Leza JC, Pazos A, Garzón J, Meana JJ, Micó JA, Desco M, et al. Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: relevance to schizophrenia. Transl Psychiatry. 2013;3:e221.PubMedCentralCrossRefPubMed
36.
Gil-Pisa I, Munarriz-Cuezva E, Ramos-Miguel A, Urigüen L, Meana JJ, García-Sevilla JA. Regulation of munc18-1 and syntaxin-1A interactive partners in schizophrenia prefrontal cortex: down-regulation of munc18-1a isoform and 75 kDa SNARE complex after antipsychotic treatment. Int J Neuropsychopharmacol. 2012;15:573–88.CrossRefPubMed
37.
Behan AT, Byrne C, Dunn MJ, Cagney G, Cotter DR. Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression. Mol Psychiatry. 2009;14:601–13.CrossRefPubMed
38.
Ramos-Miguel A, Beasley CL, Dwork AJ, Mann JJ, Rosoklija G, Barr AM, et al. Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia. Biol Psychiatry. 2014;78:361–73.CrossRefPubMed
39.
Meijer M, Cijsouw T, Toonen RF, Verhage M. Synaptic Effects of Munc18-1 Alternative Splicing in Excitatory Hippocampal Neurons. PLoS One. 2015;10:e0138950.PubMedCentralCrossRefPubMed
40.
Saitsu H, Kato M, Mizuguchi T, Hamada K, Osaka H, Tohyama J, et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet. 2008;40:782–8.CrossRefPubMed
41.
Saitsu H, Kato M, Matsumoto N. Haploinsufficiency of STXBP1 and Ohtahara syndrome. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s Basic Mechanisms of the Epilepsies. 4th ed. Bethesda (MD), USA: National Center for Biotechnology Information; 2012. p. 1–12.
42.
Hamdan FF, Gauthier J, Dobrzeniecka S, Lortie A, Mottron L, Vanasse M, et al. Intellectual disability without epilepsy associated with STXBP1 disruption. Eur J Hum Genet. 2011;19:607–9.PubMedCentralCrossRefPubMed
43.
Hamdan FF, Piton A, Gauthier J, Lortie A, Dubeau F, Dobrzeniecka S, et al. De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy. Ann Neurol. 2009;65:748–53.CrossRefPubMed
44.
Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674–82.CrossRefPubMed
45.
Deprez L, Weckhuysen S, Holmgren P, Suls A, Van Dyck T, Goossens D, et al. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology. 2010;75:1159–65.CrossRefPubMed
46.
Jacobs EH, Williams RJ, Francis PT. Cyclin-dependent kinase 5, Munc18a and Munc18-interacting protein 1/X11alpha protein up-regulation in Alzheimer’s disease. Neuroscience. 2006;138:511–22.CrossRefPubMed
47.
Donovan LE, Higginbotham L, Dammer EB, Gearing M, Rees HD, Xia Q, et al. Analysis of a membrane-enriched proteome from postmortem human brain tissue in Alzheimer’s disease. PROTEOMICS – Clin Appl. 2012;6:201–11.PubMedCentralCrossRefPubMed
48.
Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A. 1997;94(November):13287–92.PubMedCentralCrossRefPubMed
49.
Hata Y, Sudhof TC. A novel ubiquitous form of Munc-18 interacts with multiple syntaxins. Use of the yeast two-hybrid system to study interactions between proteins involved in membrane traffic. J Biol Chem. 1995;270:13022–8.CrossRefPubMed
50.
51.
52.
Okamoto M, Sudhof TC. Mints, Munc18-interacting proteins in synaptic vesicle exocytosis. J Biol Chem. 1997;272:31459–64.CrossRefPubMed
53.
Zhu Y, Ning D, Wang F, Liu C, Xu Y, Jia X, et al. Effect of thyroxine on munc-18 and syntaxin-1 expression in dorsal hippocampus of adult-onset hypothyroid rats. Eur J Histochem. 2012;56:135–41.CrossRef
54.
Chaudhry FA, Reimer RJ, Bellocchio EE, Danbolt NC, Osen KK, Edwards RH, et al. The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J Neurosci. 1998;18:9733–50.PubMed
55.
Sloviter RS. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science. 1987;235:73–6.CrossRefPubMed
56.
Wittner L, Magloczky Z, Borhegyi Z, Halasz P, Toth S, Eross L, et al. Preservation of perisomatic inhibitory input of granule cells in the epileptic human dentate gyrus. Neuroscience. 2001;108:587–600.CrossRefPubMed
57.
Bai B, Hales CM, Chen P-C, Gozal Y, Dammer EB, Fritz JJ, et al. U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease. Proc Natl Acad Sci. 2013;110:16562–7.PubMedCentralCrossRefPubMed
58.
Bell KFS, Bennett DA, Cuello AC. Paradoxical upregulation of glutamatergic presynaptic boutons during mild cognitive impairment. J Neurosci. 2007;27:10810–7.CrossRefPubMed
59.
Koliatsos VE, Kecojevic A, Troncoso JC, Gastard MC, Bennett DA, Schneider JA. Early involvement of small inhibitory cortical interneurons in Alzheimer’s disease. Acta Neuropathol. 2006;112:147–62.CrossRefPubMed
60.
61.
Canas PM, Simoes AP, Rodrigues RJ, Cunha RA. Predominant loss of glutamatergic terminal markers in a beta-amyloid peptide model of Alzheimer’s disease. Neuropharmacology. 2014;76(Pt A):51–6.CrossRefPubMed
62.
Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA. Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology. 2004;62:1148–55.CrossRefPubMed
63.
Bennett DA, Schneider JA, Tang Y, Arnold SE, Wilson RS. The effect of social networks on the relation between Alzheimer’s disease pathology and level of cognitive function in old people: a longitudinal cohort study. Lancet Neurol. 2006;5:406–12.CrossRefPubMed
64.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 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. 1984;34:939–44.CrossRefPubMed
65.
Gray EG, Whittaker VP. The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. J Anat. 1962;96:79–88.PubMedCentralPubMed
66.
Deramecourt V, Bombois S, Maurage C-A, Ghestem A, Drobecq H, Vanmechelen E, et al. Biochemical staging of synucleinopathy and amyloid deposition in dementia with Lewy bodies. J Neuropathol Exp Neurol. 2006;65:278–88.CrossRefPubMed
67.
Ohrfelt A, Zetterberg H, Andersson K, Persson R, Secic D, Brinkmalm G, et al. Identification of novel alpha-synuclein isoforms in human brain tissue by using an online nanoLC-ESI-FTICR-MS method. Neurochem Res. 2011;36:2029–42.PubMedCentralCrossRefPubMed
68.
Barakauskas VE, Beasley CL, Barr AM, Ypsilanti AR, Li H-Y, Thornton AE, et al. A novel mechanism and treatment target for presynaptic abnormalities in specific striatal regions in schizophrenia. Neuropsychopharmacology. 2010;35:1226–38.PubMedCentralCrossRefPubMed
69.
Honer WG, Hu L, Davies P. Human synaptic proteins with a heterogeneous distribution in cerebellum and visual cortex. Brain Res. 1993;609:9–20.CrossRefPubMed
70.
Mai JK, Assheuer J, Paxinos G. Atlas of the Human Brain. 3rd ed. San Diego, CA: Academic; 1997.
71.
Morrison JH, Baxter MG. The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci. 2012;13:240–50.PubMedCentralPubMed
72.
73.
Barr AM, Wu CH, Wong C, Hercher C, Töpfer E, Boyda HN, et al. Effects of chronic exercise and treatment with the antipsychotic drug olanzapine on hippocampal volume in adult female rats. Neuroscience. 2013;255:147–57.CrossRefPubMed
74.
Sawada K, Barr AM, Nakamura M, Arima K, Young CE, Dwork AJ, et al. Hippocampal complexin proteins and cognitive dysfunction in schizophrenia. Arch Gen Psychiatry. 2005;62:263–72.CrossRefPubMed
75.
Hercher C, Chopra V, Beasley CL. Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder. J Psychiatry Neurosci. 2014;39:376–85.PubMedCentralCrossRefPubMed
76.
Ramos-Miguel A, Honer WG, Boyda HN, Sawada K, Beasley CL, Procyshyn RM, et al. Exercise prevents downregulation of hippocampal presynaptic proteins following olanzapine-elicited metabolic dysregulation in rats: Distinct roles of inhibitory and excitatory terminals. Neuroscience. 2015;301:298–311.CrossRefPubMed
77.
Costes SV, Daelemans D, Cho EH, Dobbin Z, Pavlakis G, Lockett S. Automatic and quantitative measurement of protein-protein colocalization in live cells. Biophys J. 2004;86:3993–4003.PubMedCentralCrossRefPubMed
Metadata
Title
Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample
Authors
Alfredo Ramos-Miguel
Christa Hercher
Clare L. Beasley
Alasdair M. Barr
Thomas A. Bayer
Peter Falkai
Sue E. Leurgans
Julie A. Schneider
David A. Bennett
William G. Honer
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2015
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-015-0061-4

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