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01-11-2017 | Original Paper

Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits

Authors: Alain Lacampagne, Xiaoping Liu, Steven Reiken, Renaud Bussiere, Albano C. Meli, Inger Lauritzen, Andrew F. Teich, Ran Zalk, Nathalie Saint, Ottavio Arancio, Charlotte Bauer, Fabrice Duprat, Clark A. Briggs, Shreaya Chakroborty, Grace E. Stutzmann, Michael L. Shelanski, Frederic Checler, Mounia Chami, Andrew R. Marks

Published in: Acta Neuropathologica | Issue 5/2017

Abstract

The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 × Tg-AD, APP ^+/− /PS1 ^+/−). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca²⁺) leak. RyR-mediated ER Ca²⁺ leak activates Ca²⁺-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca²⁺ leak improved synaptic plasticity, normalized behavioral and cognitive functions and reduced Aβ load. Genetically altered mice with congenitally leaky RyR2 exhibited premature and severe defects in synaptic plasticity, behavior and cognitive function. These data provide a mechanism underlying leaky RyR2 channels, which could be considered as potential AD therapeutic targets.

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Adasme T, Haeger P, Paula-Lima AC, Espinoza I, Casas-Alarcon MM, Carrasco MA, Hidalgo C (2011) Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation. Proc Natl Acad Sci USA 108:3029–3034. doi:10.1073/pnas.1013580108 CrossRefPubMedPubMedCentral

Allen PB, Ouimet CC, Greengard P (1997) Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. Proc Natl Acad Sci USA 94:9956–9961CrossRefPubMedPubMedCentral

Andersson DC, Betzenhauser MJ, Reiken S, Meli AC, Umanskaya A, Xie W, Shiomi T, Zalk R, Lacampagne A, Marks AR (2011) Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. Cell Metab 14:196–207. doi:10.1016/j.cmet.2011.05.014 CrossRefPubMedPubMedCentral

Barelli H, Lebeau A, Vizzavona J, Delaere P, Chevallier N, Drouot C, Marambaud P, Ancolio K, Buxbaum JD, Khorkova O et al (1997) Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid beta peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer’s disease and cerebral amyloid angiopathy cases. Mol Med 3:695–707PubMedPubMedCentral

Bennett DA, Yu L, Yang J, Srivastava GP, Aubin C, De Jager PL (2015) Epigenomics of Alzheimer’s disease. Transl Res 165:200–220. doi:10.1016/j.trsl.2014.05.006 CrossRefPubMed

Berridge MJ (2011) Calcium signalling and Alzheimer’s disease. Neurochem Res 36:1149–1156. doi:10.1007/s11064-010-0371-4 CrossRefPubMed

Branca C, Wisely EV, Hartman LK, Caccamo A, Oddo S (2014) Administration of a selective beta2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer’s disease. Neurobiol Aging 35:2726–2735. doi:10.1016/j.neurobiolaging.2014.06.011 CrossRefPubMedPubMedCentral

Briggs CA, Schneider C, Richardson JC, Stutzmann GE (2013) beta amyloid peptide plaques fail to alter evoked neuronal calcium signals in APP/PS1 Alzheimer’s disease mice. Neurobiol Aging 34:1632–1643. doi:10.1016/j.neurobiolaging.2012.12.013 CrossRefPubMedPubMedCentral

Brillantes AB, Ondrias K, Scott A, Kobrinsky E, Ondriasova E, Moschella MC, Jayaraman T, Landers M, Ehrlich BE, Marks AR (1994) Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Cell 77:513–523CrossRefPubMed

10.

Bruno AM, Huang JY, Bennett DA, Marr RA, Hastings ML, Stutzmann GE (2012) Altered ryanodine receptor expression in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 33(1001):e1001–e1006. doi:10.1016/j.neurobiolaging.2011.03.011

11.

Chakroborty S, Briggs C, Miller MB, Goussakov I, Schneider C, Kim J, Wicks J, Richardson JC, Conklin V, Cameransi BG et al (2012) Stabilizing ER Ca(2+) Channel Function as an Early Preventative Strategy for Alzheimer’s Disease. PLoS One 7:e52056. doi:10.1371/journal.pone.0052056 CrossRefPubMedPubMedCentral

12.

Chakroborty S, Kim J, Schneider C, Jacobson C, Molgo J, Stutzmann GE (2012) Early presynaptic and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer’s disease mice. J Neurosci 32:8341–8353. doi:10.1523/JNEUROSCI.0936-12.2012 CrossRefPubMedPubMedCentral

13.

Chakroborty S, Stutzmann GE (2014) Calcium channelopathies and Alzheimer’s disease: insight into therapeutic success and failures. Eur J Pharmacol 739:83–95. doi:10.1016/j.ejphar.2013.11.012 CrossRefPubMed

14.

Chan SL, Mayne M, Holden CP, Geiger JD, Mattson MP (2000) Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J Biol Chem 275:18195–18200. doi:10.1074/jbc.M000040200 CrossRefPubMed

15.

Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK (2008) Mechanism of Ca²⁺ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58:871–883. doi:10.1016/j.neuron.2008.04.015 CrossRefPubMedPubMedCentral

16.

Colquhoun D, Hawkes AG (1982) On the stochastic properties of bursts of single ion channel openings and of clusters of bursts. Philos Trans R Soc Lond B Biol Sci 300:1–59CrossRefPubMed

17.

Copello JA, Barg S, Onoue H, Fleischer S (1997) Heterogeneity of Ca²⁺ gating of skeletal muscle and cardiac ryanodine receptors. Biophys J 73:141–156. doi:10.1016/S0006-3495(97)78055-X CrossRefPubMedPubMedCentral

18.

Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, Arnold SE, Attems J, Beach TG, Bigio EH et al (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 CrossRefPubMedPubMedCentral

19.

Dang V, Medina B, Das D, Moghadam S, Martin KJ, Lin B, Naik P, Patel D, Nosheny R, Wesson Ashford J et al (2014) Formoterol, a long-acting beta2 adrenergic agonist, improves cognitive function and promotes dendritic complexity in a mouse model of Down syndrome. Biol Psychiatry 75:179–188. doi:10.1016/j.biopsych.2013.05.024 CrossRefPubMed

20.

Del Prete D, Checler F, Chami M (2014) Ryanodine receptors: physiological function and deregulation in Alzheimer disease. Mol Neurodegener 9:21. doi:10.1186/1750-1326-9-21 CrossRefPubMedPubMedCentral

21.

Dobarro M, Gerenu G, Ramirez MJ (2013) Propranolol reduces cognitive deficits, amyloid and tau pathology in Alzheimer’s transgenic mice. Int J Neuropsychopharmacol 16:2245–2257. doi:10.1017/S1461145713000631 CrossRefPubMed

22.

Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D et al (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–713. doi:10.1038/383710a0 CrossRefPubMed

23.

Echeverria V, Ducatenzeiler A, Chen CH, Cuello AC (2005) Endogenous beta-amyloid peptide synthesis modulates cAMP response element-regulated gene expression in PC12 cells. Neuroscience 135:1193–1202. doi:10.1016/j.neuroscience.2005.06.057 CrossRefPubMed

24.

Etcheberrigaray R, Hirashima N, Nee L, Prince J, Govoni S, Racchi M, Tanzi RE, Alkon DL (1998) Calcium responses in fibroblasts from asymptomatic members of Alzheimer’s disease families. Neurobiol Dis 5:37–45. doi:10.1006/nbdi.1998.0176 CrossRefPubMed

25.

Etkin A, Alarcon JM, Weisberg SP, Touzani K, Huang YY, Nordheim A, Kandel ER (2006) A role in learning for SRF: deletion in the adult forebrain disrupts LTD and the formation of an immediate memory of a novel context. Neuron 50:127–143. doi:10.1016/j.neuron.2006.03.013 CrossRefPubMed

26.

Feng J, Yan Z, Ferreira A, Tomizawa K, Liauw JA, Zhuo M, Allen PB, Ouimet CC, Greengard P (2000) Spinophilin regulates the formation and function of dendritic spines. Proc Natl Acad Sci USA 97:9287–9292CrossRefPubMedPubMedCentral

27.

Flammang B, Pardossi-Piquard R, Sevalle J, Debayle D, Dabert-Gay AS, Thevenet A, Lauritzen I, Checler F (2012) Evidence that the amyloid-beta protein precursor intracellular domain, AICD, derives from beta-secretase-generated C-terminal fragment. J Alzheimers Dis 30:145–153. doi:10.3233/JAD-2012-112186 PubMed

28.

Flucher BE, Andrews SB, Fleischer S, Marks AR, Caswell A, Powell JA (1993) Triad formation: organization and function of the sarcoplasmic reticulum calcium release channel and triadin in normal and dysgenic muscle in vitro. J Cell Biol 123:1161–1174CrossRefPubMed

29.

Francis YI, Fa M, Ashraf H, Zhang H, Staniszewski A, Latchman DS, Arancio O (2009) Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer’s disease. J Alzheimers Dis 18:131–139. doi:10.3233/JAD-2009-1134 CrossRefPubMed

30.

Gapp K, Woldemichael BT, Bohacek J, Mansuy IM (2014) Epigenetic regulation in neurodevelopment and neurodegenerative diseases. Neuroscience 264:99–111. doi:10.1016/j.neuroscience.2012.11.040 CrossRefPubMed

31.

Ghosh D, LeVault KR, Barnett AJ, Brewer GJ (2012) A reversible early oxidized redox state that precedes macromolecular ROS damage in aging nontransgenic and 3 × Tg-AD mouse neurons. J Neurosci 32:5821–5832. doi:10.1523/JNEUROSCI.6192-11.2012 CrossRefPubMedPubMedCentral

32.

Giannini G, Conti A, Mammarella S, Scrobogna M, Sorrentino V (1995) The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. J Cell Biol 128:893–904CrossRefPubMed

33.

Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O (2006) Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell 126:775–788. doi:10.1016/j.cell.2006.06.046 CrossRefPubMed

34.

Goslin K (1991) Rat hippocampal neurons in low-density culture. MIT Press, Cambridge, pp 251–281

35.

Goussakov I, Miller MB, Stutzmann GE (2010) NMDA-mediated Ca(2 +) influx drives aberrant ryanodine receptor activation in dendrites of young Alzheimer’s disease mice. J Neurosci 30:12128–12137. doi:10.1523/JNEUROSCI.2474-10.2010 CrossRefPubMedPubMedCentral

36.

Heck A, Fastenrath M, Coynel D, Auschra B, Bickel H, Freytag V, Gschwind L, Hartmann F, Jessen F, Kaduszkiewicz Het al (2015) Genetic analysis of association between calcium signaling and hippocampal activation, memory performance in the young and old, and risk for sporadic Alzheimer disease. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2015.1309

37.

Hidalgo C, Carrasco MA (2011) Redox control of brain calcium in health and disease. Antioxid Redox Signal 14:1203–1207. doi:10.1089/ars.2010.3711 CrossRefPubMed

38.

Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102CrossRefPubMed

39.

Igbavboa U, Johnson-Anuna LN, Rossello X, Butterick TA, Sun GY, Wood WG (2006) Amyloid beta-protein1-42 increases cAMP and apolipoprotein E levels which are inhibited by beta1 and beta2-adrenergic receptor antagonists in mouse primary astrocytes. Neuroscience 142:655–660. doi:10.1016/j.neuroscience.2006.06.056 CrossRefPubMed

40.

Lalonde R, Kim HD, Maxwell JA, Fukuchi K (2005) Exploratory activity and spatial learning in 12-month-old APP(695)SWE/co+ PS1/DeltaE9 mice with amyloid plaques. Neurosci Lett 390:87–92. doi:10.1016/j.neulet.2005.08.028 CrossRefPubMed

41.

Lauritzen I, Pardossi-Piquard R, Bauer C, Brigham E, Abraham JD, Ranaldi S, Fraser P, St-George-Hyslop P, Le Thuc O, Espin V et al (2012) The beta-secretase-derived C-terminal fragment of betaAPP, C99, but not Abeta, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J Neurosci 32:16243–16255a. doi:10.1523/JNEUROSCI.2775-12.2012 CrossRefPubMedPubMedCentral

42.

LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184. doi:10.1146/annurev.neuro.23.1.155 CrossRefPubMed

43.

Leissring MA, Murphy MP, Mead TR, Akbari Y, Sugarman MC, Jannatipour M, Anliker B, Muller U, Saftig P, De Strooper B et al (2002) A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP. Proc Natl Acad Sci USA 99:4697–4702. doi:10.1073/pnas.072033799 CrossRefPubMedPubMedCentral

44.

Leissring MA, Parker I, LaFerla FM (1999) Presenilin-2 mutations modulate amplitude and kinetics of inositol 1, 4,5-trisphosphate-mediated calcium signals. J Biol Chem 274:32535–32538CrossRefPubMed

45.

Li R, Lindholm K, Yang LB, Yue X, Citron M, Yan R, Beach T, Sue L, Sabbagh M, Cai H et al (2004) Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci USA 101:3632–3637. doi:10.1073/pnas.0205689101 CrossRefPubMedPubMedCentral

46.

Li S, Jin M, Zhang D, Yang T, Koeglsperger T, Fu H, Selkoe DJ (2013) Environmental novelty activates beta2-adrenergic signaling to prevent the impairment of hippocampal LTP by Abeta oligomers. Neuron 77:929–941. doi:10.1016/j.neuron.2012.12.040 CrossRefPubMedPubMedCentral

47.

Liang L, Wei H (2015) Dantrolene, a treatment for Alzheimer disease? Alzheimer Dis Assoc Disord 29:1–5. doi:10.1097/WAD.0000000000000076 CrossRefPubMedPubMedCentral

48.

Liu X, Betzenhauser MJ, Reiken S, Meli AC, Xie W, Chen BX, Arancio O, Marks AR (2012) Role of leaky neuronal ryanodine receptors in stress- induced cognitive dysfunction. Cell 150:1055–1067. doi:10.1016/j.cell.2012.06.052 CrossRefPubMedPubMedCentral

49.

Marambaud P, Ancolio K, Alves da Costa C, Checler F (1999) Effect of protein kinase A inhibitors on the production of Abeta40 and Abeta42 by human cells expressing normal and Alzheimer’s disease-linked mutated betaAPP and presenilin 1. Br J Pharmacol 126:1186–1190. doi:10.1038/sj.bjp.0702406 CrossRefPubMedPubMedCentral

50.

Marks AR (1997) Intracellular calcium-release channels: regulators of cell life and death. Am J Physiol 272:H597–H605PubMed

51.

Marx SO, Reiken S, Hisamatsu Y, Gaburjakova M, Gaburjakova J, Yang YM, Rosemblit N, Marks AR (2001) Phosphorylation-dependent regulation of ryanodine receptors: a novel role for leucine/isoleucine zippers. J Cell Biol 153:699–708CrossRefPubMedPubMedCentral

52.

Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101:365–376CrossRefPubMed

53.

Moolman DL, Vitolo OV, Vonsattel JP, Shelanski ML (2004) Dendrite and dendritic spine alterations in Alzheimer models. J Neurocytol 33:377–387. doi:10.1023/B:NEUR.0000044197.83514.64 CrossRefPubMed

54.

Ni Y, Zhao X, Bao G, Zou L, Teng L, Wang Z, Song M, Xiong J, Bai Y, Pei G (2006) Activation of beta2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation. Nat Med 12:1390–1396. doi:10.1038/nm1485 CrossRefPubMed

55.

Nicholls RE, Alarcon JM, Malleret G, Carroll RC, Grody M, Vronskaya S, Kandel ER (2008) Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility. Neuron 58:104–117. doi:10.1016/j.neuron.2008.01.039 CrossRefPubMed

56.

Niu Y, Su Z, Zhao C, Song B, Zhang X, Zhao N, Shen X, Gong Y (2009) Effect of amyloid beta on capacitive calcium entry in neural 2a cells. Brain Res Bull 78:152–157. doi:10.1016/j.brainresbull.2008.10.003 CrossRefPubMed

57.

Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421CrossRefPubMed

58.

Oules B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, Moreno S, Paterlini-Brechot P, Trebak M, Checler F et al (2012) Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci 32:11820–11834. doi:10.1523/JNEUROSCI.0875-12.2012 CrossRefPubMedPubMedCentral

59.

Palavicini JP, Wang H, Bianchi E, Xu S, Rao JS, Kang DE, Lakshmana MK (2013) RanBP9 aggravates synaptic damage in the mouse brain and is inversely correlated to spinophilin levels in Alzheimer’s brain synaptosomes. Cell Death Dis 4:e667. doi:10.1038/cddis.2013.183 CrossRefPubMedPubMedCentral

60.

Paula-Lima AC, Adasme T, SanMartin C, Sebollela A, Hetz C, Carrasco MA, Ferreira ST, Hidalgo C (2011) Amyloid beta-peptide oligomers stimulate RyR-mediated Ca²⁺ release inducing mitochondrial fragmentation in hippocampal neurons and prevent RyR-mediated dendritic spine remodeling produced by BDNF. Antioxid Redox Signal 14:1209–1223. doi:10.1089/ars.2010.3287 CrossRefPubMed

61.

Paula-Lima AC, Hidalgo C (2013) Amyloid beta-peptide oligomers, ryanodine receptor-mediated Ca(2+) release, and Wnt-5a/Ca(2+) signaling: opposing roles in neuronal mitochondrial dynamics? Front Cell Neurosci 7:120. doi:10.3389/fncel.2013.00120 CrossRefPubMedPubMedCentral

62.

Paylor R, Tracy R, Wehner J, Rudy JW (1994) DBA/2 and C57BL/6 mice differ in contextual fear but not auditory fear conditioning. Behav Neurosci 108:810–817CrossRefPubMed

63.

Peng J, Liang G, Inan S, Wu Z, Joseph DJ, Meng Q, Peng Y, Eckenhoff MF, Wei H (2012) Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett 516:274–279. doi:10.1016/j.neulet.2012.04.008 CrossRefPubMedPubMedCentral

64.

Pilpel Y, Segal M (2004) Activation of PKC induces rapid morphological plasticity in dendrites of hippocampal neurons via Rac and Rho-dependent mechanisms. Eur J Neurosci 19:3151–3164. doi:10.1111/j.0953-816X.2004.03380.x CrossRefPubMed

65.

Popugaeva E, Bezprozvanny I (2013) Role of endoplasmic reticulum Ca²⁺ signaling in the pathogenesis of Alzheimer disease. Front Mol Neurosci 6:29. doi:10.3389/fnmol.2013.00029 CrossRefPubMedPubMedCentral

66.

Prapong T, Uemura E, Hsu WH (2001) G protein and cAMP-dependent protein kinase mediate amyloid beta-peptide inhibition of neuronal glucose uptake. Experimental neurology 167:59–64. doi:10.1006/exnr.2000.7519 CrossRefPubMed

67.

Reyes M, Stanton PK (1996) Induction of hippocampal long-term depression requires release of Ca²⁺ from separate presynaptic and postsynaptic intracellular stores. J Neurosci 16:5951–5960PubMed

68.

Rosenberg PB, Mielke MM, Tschanz J, Cook L, Corcoran C, Hayden KM, Norton M, Rabins PV, Green RC, Welsh-Bohmer KA et al (2008) Effects of cardiovascular medications on rate of functional decline in Alzheimer disease. Am J Geriatr Psychiatry 16:883–892. doi:10.1097/JGP.0b013e318181276a CrossRefPubMedPubMedCentral

69.

Saito K, Elce JS, Hamos JE, Nixon RA (1993) Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci USA 90:2628–2632CrossRefPubMedPubMedCentral

70.

Santulli G, Marks AR (2015) Essential Roles of intracellular calcium release channels in muscle, brain, metabolism, and aging. Curr Mol Pharmacol 8:206–222CrossRefPubMed

71.

Schubert V, Da Silva JS, Dotti CG (2006) Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor-dependent manner. J Cell Biol 172:453–467. doi:10.1083/jcb.200506136 CrossRefPubMedPubMedCentral

72.

Shan J, Betzenhauser MJ, Kushnir A, Reiken S, Meli AC, Wronska A, Dura M, Chen BX, Marks AR (2010) Role of chronic ryanodine receptor phosphorylation in heart failure and beta-adrenergic receptor blockade in mice. J Clin Invest 120:4375–4387. doi:10.1172/JCI37649 CrossRefPubMedPubMedCentral

73.

Shan J, Kushnir A, Betzenhauser MJ, Reiken S, Li J, Lehnart SE, Lindegger N, Mongillo M, Mohler PJ, Marks AR (2010) Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice. J Clin Invest 120:4388–4398. doi:10.1172/JCI32726 CrossRefPubMedPubMedCentral

74.

Shilling D, Muller M, Takano H, Mak DO, Abel T, Coulter DA, Foskett JK (2014) Suppression of InsP3 receptor-mediated Ca²⁺ signaling alleviates mutant presenilin-linked familial Alzheimer’s disease pathogenesis. J Neurosci 34:6910–6923. doi:10.1523/JNEUROSCI.5441-13.2014 CrossRefPubMedPubMedCentral

75.

Shrestha BR, Vitolo OV, Joshi P, Lordkipanidze T, Shelanski M, Dunaevsky A (2006) Amyloid beta peptide adversely affects spine number and motility in hippocampal neurons. Mol Cell Neurosci 33:274–282. doi:10.1016/j.mcn.2006.07.011 CrossRefPubMed

76.

Smith DL, Pozueta J, Gong B, Arancio O, Shelanski M (2009) Reversal of long-term dendritic spine alterations in Alzheimer disease models. Proc Natl Acad Sci USA 106:16877–16882. doi:10.1073/pnas.0908706106 CrossRefPubMedPubMedCentral

77.

Stutzmann GE, Caccamo A, LaFerla FM, Parker I (2004) Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin1 results in exaggerated Ca²⁺ signals and altered membrane excitability. J Neurosci 24:508–513. doi:10.1523/JNEUROSCI.4386-03.2004 CrossRefPubMed

78.

Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I (2006) Enhanced ryanodine receptor recruitment contributes to Ca²⁺ disruptions in young, adult, and aged Alzheimer’s disease mice. J Neurosci 26:5180–5189. doi:10.1523/JNEUROSCI.0739-06.2006 CrossRefPubMed

79.

Supnet C, Grant J, Kong H, Westaway D, Mayne M (2006) Amyloid-beta-(1-42) increases ryanodine receptor-3 expression and function in neurons of TgCRND8 mice. J Biol Chem 281:38440–38447. doi:10.1074/jbc.M606736200 CrossRefPubMed

80.

Tashiro A, Minden A, Yuste R (2000) Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb Cortex 10:927–938CrossRefPubMed

81.

Texido L, Martin-Satue M, Alberdi E, Solsona C, Matute C (2011) Amyloid beta peptide oligomers directly activate NMDA receptors. Cell Calcium 49:184–190. doi:10.1016/j.ceca.2011.02.001 CrossRefPubMed

82.

Unni VK, Zakharenko SS, Zablow L, DeCostanzo AJ, Siegelbaum SA (2004) Calcium release from presynaptic ryanodine-sensitive stores is required for long-term depression at hippocampal CA3-CA3 pyramidal neuron synapses. J Neurosci 24:9612–9622. doi:10.1523/JNEUROSCI.5583-03.2004 CrossRefPubMed

83.

von Bernhardi R, Eugenin J (2012) Alzheimer’s disease: redox dysregulation as a common denominator for diverse pathogenic mechanisms. Antioxid Redox Signal 16:974–1031. doi:10.1089/ars.2011.4082 CrossRef

84.

Wang D, Govindaiah G, Liu R, De Arcangelis V, Cox CL, Xiang YK (2010) Binding of amyloid beta peptide to beta2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity. FASEB J 24:3511–3521. doi:10.1096/fj.10-156661 CrossRefPubMedPubMedCentral

85.

Wehrens XH, Lehnart SE, Reiken SR, Deng SX, Vest JA, Cervantes D, Coromilas J, Landry DW, Marks AR (2004) Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science 304:292–296. doi:10.1126/science.1094301 CrossRefPubMed

86.

Wisely EV, Xiang YK, Oddo S (2014) Genetic suppression of beta2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies. Hum Mol Genet 23:4024–4034. doi:10.1093/hmg/ddu116 CrossRefPubMedPubMedCentral

87.

Wu B, Yamaguchi H, Lai FA, Shen J (2013) Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons. Proc Natl Acad Sci USA 110:15091–15096. doi:10.1073/pnas.1304171110 CrossRefPubMedPubMedCentral

88.

Yang LB, Lindholm K, Yan R, Citron M, Xia W, Yang XL, Beach T, Sue L, Wong P, Price D et al (2003) Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 9:3–4. doi:10.1038/nm0103-3 CrossRefPubMed

89.

Yu JT, Tan L, Ou JR, Zhu JX, Liu K, Song JH, Sun YP (2008) Polymorphisms at the beta2-adrenergic receptor gene influence Alzheimer’s disease susceptibility. Brain Res 1210:216–222. doi:10.1016/j.brainres.2008.03.019 CrossRefPubMed

90.

Yu NN, Wang XX, Yu JT, Wang ND, Lu RC, Miao D, Tian Y, Tan L (2010) Blocking beta2-adrenergic receptor attenuates acute stress-induced amyloid beta peptides production. Brain Res 1317:305–310. doi:10.1016/j.brainres.2009.12.087 CrossRefPubMed

91.

Zhang H, Liu J, Sun S, Pchitskaya E, Popugaeva E, Bezprozvanny I (2015) Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer’s disease. J Alzheimers Dis 45:561–580. doi:10.3233/JAD-142427 PubMedPubMedCentral

92.

Zhang H, Sun S, Herreman A, De Strooper B, Bezprozvanny I (2010) Role of presenilins in neuronal calcium homeostasis. J Neurosci 30:8566–8580. doi:10.1523/JNEUROSCI.1554-10.2010 CrossRefPubMedPubMedCentral

Title: Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits
Authors: Alain Lacampagne
Xiaoping Liu
Steven Reiken
Renaud Bussiere
Albano C. Meli
Inger Lauritzen
Andrew F. Teich
Ran Zalk
Nathalie Saint
Ottavio Arancio
Charlotte Bauer
Fabrice Duprat
Clark A. Briggs
Shreaya Chakroborty
Grace E. Stutzmann
Michael L. Shelanski
Frederic Checler
Mounia Chami
Andrew R. Marks
Publication date: 01-11-2017
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1733-7

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

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