Reversal of Calcium Dysregulation as Potential Approach for Treating Alzheimer's Disease

Elena       Popugaeva; Daria       Chernyuk; Ilya       Bezprozvanny
Abstract

Despite decades of research and effort, there is still no effective disease-modifying treatment for Alzheimer’s Disease (AD). Most of the recent AD clinical trials were targeting amyloid pathway, but all these trials failed. Although amyloid pathology is a hallmark and defining feature of AD, targeting the amyloid pathway has been very challenging due to low efficacy and serious side effects. Alternative approaches or mechanisms for our understanding of the major cause of memory loss in AD need to be considered as potential therapeutic targets. Increasing studies suggest that Ca2+ dysregulation in AD plays an important role in AD pathology and is associated with other AD abnormalities, such as excessive inflammation, increased ROS, impaired autophagy, neurodegeneration, synapse, and cognitive dysfunction. Ca2+ dysregulation in cytosolic space, Endoplasmic Reticulum (ER) and mitochondria have been reported in the context of various AD models. Drugs or strategies, to correct the Ca2+ dysregulation in AD, have been demonstrated to be promising as an approach for the treatment of AD in preclinical models. This review will discuss the mechanisms of Ca2+ dysregulation in AD and associated pathology and discuss potential approaches or strategies to develop novel drugs for the treatment of AD by targeting Ca2+ dysregulation.
Keywords: Alzheimer's disease, calcium hypothesis, nSOCE, therapeutic agents, cytosolic space, endoplasmic reticulum (ER).
[1] 
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol  1991; 82(4): 239-59.
[http://dx.doi.org/10.1007/BF00308809] [PMID: 1759558] 
[2] 
Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science  1993; 261(5123): 921-3.
[http://dx.doi.org/10.1126/science.8346443] [PMID: 8346443] 
[3] 
Strittmatter WJ, Weisgraber KH, Huang DY, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: Isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA  1993; 90(17): 8098-102.
[http://dx.doi.org/10.1073/pnas.90.17.8098] [PMID: 8367470] 
[4] 
Castellano JM, Kim J, Stewart FR, et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med  2011; 3(89)89ra57
[http://dx.doi.org/10.1126/scitranslmed.3002156] [PMID: 21715678] 
[5] 
Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron  2009; 63(3): 287-303.
[http://dx.doi.org/10.1016/j.neuron.2009.06.026] [PMID: 19679070] 
[6] 
Verghese PB, Castellano JM, Garai K, et al. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci USA  2013; 110(19): E1807-16.
[http://dx.doi.org/10.1073/pnas.1220484110] [PMID: 23620513] 
[7] 
Berlau DJ, Corrada MM, Head E, Kawas CH. APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology  2009; 72(9): 829-34.
[http://dx.doi.org/10.1212/01.wnl.0000343853.00346.a4] [PMID: 19255410] 
[8] 
Forabosco P, Ramasamy A, Trabzuni D, et al. Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol Aging  2013; 34(12): 2699-714.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.05.001] [PMID: 23855984] 
[9] 
Jay TR, Miller CM, Cheng PJ, et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med  2015; 212(3): 287-95.
[http://dx.doi.org/10.1084/jem.20142322] [PMID: 25732305] 
[10] 
Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature  2002; 416(6880): 535-9.
[http://dx.doi.org/10.1038/416535a] [PMID: 11932745] 
[11] 
Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem  2005; 280(17): 17294-300.
[PMID: 15722360] 
[12] 
Demuro A, Parker I, Stutzmann GE. Calcium signaling and amyloid toxicity in Alzheimer disease. J Biol Chem  2010; 285(17): 12463-8.
[http://dx.doi.org/10.1074/jbc.R109.080895] [PMID: 20212036] 
[13] 
Demuro A, Parker I. Cytotoxicity of intracellular aβ42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate. J Neurosci  2013; 33(9): 3824-33.
[http://dx.doi.org/10.1523/JNEUROSCI.4367-12.2013] [PMID: 23447594] 
[14] 
Deshpande A, Mina E, Glabe C, Busciglio J. Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons. J Neurosci  2006; 26(22): 6011-8.
[http://dx.doi.org/10.1523/JNEUROSCI.1189-06.2006] [PMID: 16738244] 
[15] 
Simakova O, Arispe NJ. The cell-selective neurotoxicity of the Alzheimer’s Abeta peptide is determined by surface phosphatidylserine and cytosolic ATP levels. Membrane binding is required for Abeta toxicity. J Neurosci  2007; 27(50): 13719-29.
[http://dx.doi.org/10.1523/JNEUROSCI.3006-07.2007] [PMID: 18077683] 
[16] 
Bezprozvanny I, Mattson MP. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci  2008; 31(9): 454-63.
[http://dx.doi.org/10.1016/j.tins.2008.06.005] [PMID: 18675468] 
[17] 
Green KN, Demuro A, Akbari Y, et al. SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol  2008; 181(7): 1107-16.
[http://dx.doi.org/10.1083/jcb.200706171] [PMID: 18591429] 
[18] 
Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ. Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron  2008; 59(2): 214-25.
[http://dx.doi.org/10.1016/j.neuron.2008.06.008] [PMID: 18667150] 
[19] 
Huang LK, Chao SP, Hu CJ. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci  2020; 27(1): 18.
[http://dx.doi.org/10.1186/s12929-019-0609-7] [PMID: 31906949] 
[20] 
Lovestone S, Boada M, Dubois B, et al. ARGO investigators. A phase II trial of tideglusib in Alzheimer’s disease. J Alzheimers Dis  2015; 45(1): 75-88.
[http://dx.doi.org/10.3233/JAD-141959] [PMID: 25537011] 
[21] 
Medina M. An Overview on the clinical development of tau-based therapeutics. Int J Mol Sci  2018; 19(4)E1160
[http://dx.doi.org/10.3390/ijms19041160] [PMID: 29641484] 
[22] 
Bush AI. The metal theory of Alzheimer’s disease. J Alzheimers Dis  2013; 33(1): S277-81.
[http://dx.doi.org/10.3233/JAD-2012-129011] [PMID: 22635102] 
[23] 
Basun H, Forssell LG, Wetterberg L, Winblad B. Metals and trace elements in plasma and cerebrospinal fluid in normal aging and Alzheimer’s disease. J Neural Transm Park Dis Dement Sect  1991; 3(4): 231-58.
[PMID: 1772577] 
[24] 
Salvador GA, Uranga RM, Giusto NM. Iron and mechanisms of neurotoxicity. Int J Alzheimers Dis  2010; 2011720658
[PMID: 21234369] 
[25] 
Ho M, Hoke DE, Chua YJ, et al. Effect of metal chelators on γ-secretase indicates that calcium and magnesium ions facilitate cleavage of Alzheimer amyloid precursor substrate. Int J Alzheimers Dis  2010; 2011950932
[PMID: 21253550] 
[26] 
Yan T, Ding F, Zhao Y. Integrated identification of key genes and pathways in Alzheimer’s disease via comprehensive bioinformatical analyses. Hereditas  2019; 156: 25.
[http://dx.doi.org/10.1186/s41065-019-0101-0] [PMID: 31346329] 
[27] 
Guney E, Oliva B. Exploiting protein-protein interaction networks for genome-wide disease-gene prioritization. PLoS One  2012; 7(9)e43557
[http://dx.doi.org/10.1371/journal.pone.0043557] [PMID: 23028459] 
[28] 
Khachaturian ZS. Calcium, membranes, aging, and Alzheimer’s disease. Introduction and overview. Ann N Y Acad Sci  1989; 568: 1-4.
[http://dx.doi.org/10.1111/j.1749-6632.1989.tb12485.x] [PMID: 2629579] 
[29] 
Thibault O, Gant JC, Landfield PW. Expansion of the calcium hypothesis of brain aging and Alzheimer’s disease: Minding the store. Aging Cell  2007; 6(3): 307-17.
[http://dx.doi.org/10.1111/j.1474-9726.2007.00295.x] [PMID: 17465978] 
[30] 
Berridge MJ. Calcium hypothesis of Alzheimer’s disease. Pflugers Arch 2009.
[PMID: 19795132] 
[31] 
Bezprozvanny IB. Calcium signaling and neurodegeneration. Acta Naturae  2010; 2(1): 72-82.
[http://dx.doi.org/10.32607/20758251-2010-2-1-72-80] [PMID: 22649630] 
[32] 
Popugaeva E, Vlasova OL, Bezprozvanny I. Restoring calcium homeostasis to treat Alzheimer’s disease: A future perspective. Neurodegener Dis Manag  2015; 5(5): 395-8.
[http://dx.doi.org/10.2217/nmt.15.36] [PMID: 26477700] 
[33] 
Alzheimer's Association Calcium Hypothesis W. Calcium Hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimer's Demen: J Alzheimer's Assoc   2017; 13(2):  178-82 e17..
[34] 
Foster TC, Kyritsopoulos C, Kumar A. Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer's disease.  Behav Brain research   2017;  322(Pt B): 223-32.
[http://dx.doi.org/10.1016/j.bbr.2016.05.012] 
[35] 
Mota SI, Ferreira IL, Rego AC. Dysfunctional synapse in Alzheimer's disease - a focus on NMDA receptors. Neuropharmacology   2014;  76(Pt A):  16-26.
[36] 
Zhang Y, Li P, Feng J, Wu M. Dysfunction of NMDA receptors in Alzheimer’s disease. Neurol Sci  2016; 37(7): 1039-47.
[http://dx.doi.org/10.1007/s10072-016-2546-5] [PMID: 26971324] 
[37] 
Anekonda TS, Quinn JF, Harris C, Frahler K, Wadsworth TL, Woltjer RL. L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer’s disease. Neurobiol Dis  2011; 41(1): 62-70.
[http://dx.doi.org/10.1016/j.nbd.2010.08.020] [PMID: 20816785] 
[38] 
Renner M, Lacor PN, Velasco PT, et al. Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron  2010; 66(5): 739-54.
[http://dx.doi.org/10.1016/j.neuron.2010.04.029] [PMID: 20547131] 
[39] 
Thomas SJ, Grossberg GT. Memantine: A review of studies into its safety and efficacy in treating Alzheimer’s disease and other dementias. Clin Interv Aging  2009; 4: 367-77.
[PMID: 19851512] 
[40] 
Talantova M, Sanz-Blasco S, Zhang X, et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci USA  2013; 110(27): E2518-27.
[http://dx.doi.org/10.1073/pnas.1306832110] [PMID: 23776240] 
[41] 
Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry  2000; 47(4): 351-4.
[http://dx.doi.org/10.1016/S0006-3223(99)00230-9] [PMID: 10686270] 
[42] 
Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry  2013; 74(4): 250-6.
[http://dx.doi.org/10.1016/j.biopsych.2012.06.022] [PMID: 22840761] 
[43] 
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med  2016; 22(3): 238-49.
[http://dx.doi.org/10.1038/nm.4050] [PMID: 26937618] 
[44] 
Smalheiser NR. Ketamine: A neglected therapy for Alzheimer disease. Front Aging Neurosci  2019; 11: 186.
[http://dx.doi.org/10.3389/fnagi.2019.00186] [PMID: 31396078] 
[45] 
Forette F, Seux ML, Staessen JA, et al. Systolic Hypertension in Europe Investigators. The prevention of dementia with antihypertensive treatment: New evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med  2002; 162(18): 2046-52.
[http://dx.doi.org/10.1001/archinte.162.18.2046] [PMID: 12374512] 
[46] 
Zhang H, Wu L, Pchitskaya E, et al. Neuronal store-operated calcium entry and mushroom spine loss in APP knock-in mouse model of Alzheimer’s disease. J Neurosci  2015; 35(39): 13275-86.
[47] 
Arispe N, Rojas E, Pollard HB. Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: Blockade by tromethamine and aluminum. Proc Natl Acad Sci USA  1993; 90(2): 567-71.
[http://dx.doi.org/10.1073/pnas.90.2.567] [PMID: 8380642] 
[48] 
Hartigan JA, Johnson GV. Transient increases in intracellular calcium result in prolonged site-selective increases in Tau phosphorylation through a glycogen synthase kinase 3beta-dependent pathway. J Biol Chem  1999; 274(30): 21395-401.
[http://dx.doi.org/10.1074/jbc.274.30.21395] [PMID: 10409701] 
[49] 
Gómez-Ramos A, Díaz-Hernández M, Rubio A, Miras-Portugal MT, Avila J. Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol Cell Neurosci  2008; 37(4): 673-81.
[http://dx.doi.org/10.1016/j.mcn.2007.12.010] [PMID: 18272392] 
[50] 
Wadhwani AR, Affaneh A, Van Gulden S, Kessler JA. Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease. Ann Neurol  2019; 85(5): 726-39.
[http://dx.doi.org/10.1002/ana.25455] [PMID: 30840313] 
[51] 
Qiu Z, Crutcher KA, Hyman BT, Rebeck GW. ApoE isoforms affect neuronal N-methyl-D-aspartate calcium responses and toxicity via receptor-mediated processes. Neuroscience  2003; 122(2): 291-303.
[http://dx.doi.org/10.1016/j.neuroscience.2003.08.017] [PMID: 14614897] 
[52] 
Veinbergs I, Everson A, Sagara Y, Masliah E. Neurotoxic effects of apolipoprotein E4 are mediated via dysregulation of calcium homeostasis. J Neurosci Res  2002; 67(3): 379-87.
[http://dx.doi.org/10.1002/jnr.10138] [PMID: 11813243] 
[53] 
Aono M, Bennett ER, Kim KS, et al. Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures. Neuroscience  2003; 116(2): 437-45.
[http://dx.doi.org/10.1016/S0306-4522(02)00709-1] [PMID: 12559098] 
[54] 
Popugaeva EP,  Zhang H, Vlasova O, Bezprozvanny I. STIM2 protects  mushroom spines from amyloid synaptotoxicity. Mol Neurodegener  2015; 10: 37.
[55] 
Popugaeva E, Pchitskaya E, Bezprozvanny I. Dysregulation of neuronal calcium homeostasis in Alzheimer’s disease - a therapeutic opportunity? Biochem Biophys Res Commun  2016; 83(4): 998-1004.
[PMID: 27641664] 
[56] 
Briggs CA, Chakroborty S, Stutzmann GE. Emerging pathways driving early synaptic pathology in Alzheimer’s disease. Biochem Biophys Res Commun  2017; 483(4): 988-97.
[http://dx.doi.org/10.1016/j.bbrc.2016.09.088] [PMID: 27659710] 
[57] 
Chakroborty S, Stutzmann GE. Calcium channelopathies and Alzheimer’s disease: Insight into therapeutic success and failures. Eur J Pharmacol  2014; 739: 83-95.
[http://dx.doi.org/10.1016/j.ejphar.2013.11.012] 
[58] 
Karran E, De Strooper B. The amyloid cascade hypothesis: Are we poised for success or failure? J Neurochem  2016; 139(2): 237-52.
[http://dx.doi.org/10.1111/jnc.13632] [PMID: 27255958] 
[59] 
De Strooper B. Lessons from a failed γ-secretase Alzheimer trial. Cell  2014; 159(4): 721-6.
[http://dx.doi.org/10.1016/j.cell.2014.10.016] [PMID: 25417150] 
[60] 
Wagner SL, Rynearson KD, Duddy SK, et al. Pharmacological and toxicological properties of the potent oral γ-secretase modulator BPN-15606. J Pharmacol Exp Ther  2017; 362(1): 31-44.
[http://dx.doi.org/10.1124/jpet.117.240861] [PMID: 28416568] 
[61] 
Yang G, Zhou R, Zhou Q, et al. Structural basis of Notch recognition by human γ-secretase. Nature  2019; 565(7738): 192-7.
[http://dx.doi.org/10.1038/s41586-018-0813-8] [PMID: 30598546] 
[62] 
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science  2019; 363(6428)eaaw0930
[http://dx.doi.org/10.1126/science.aaw0930] [PMID: 30630874] 
[63] 
Hsiao CC, Rombouts F, Gijsen HJM. New evolutions in the BACE1 inhibitor field from 2014 to 2018. Bioorg Med Chem Lett  2019; 29(6): 761-77.
[http://dx.doi.org/10.1016/j.bmcl.2018.12.049] [PMID: 30709653] 
[64] 
Popugaeva E, Bezprozvanny I. Can the calcium hypothesis explain synaptic loss in Alzheimer’s disease? Neurodegener Dis  2014; 13(2-3): 139-41.
[http://dx.doi.org/10.1159/000354778] [PMID: 24080896] 
[65] 
Chakroborty S, Stutzmann GE. Calcium channelopathies and Alzheimer’s disease: Insight into therapeutic success and failures. Eur J Pharmacol  2014; 739: 83-95.
[PMID: 24316360] 
[66] 
Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I. Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer’s disease mice. J Neurosci  2006; 26(19): 5180-9.
[http://dx.doi.org/10.1523/JNEUROSCI.0739-06.2006] [PMID: 16687509] 
[67] 
Chakroborty S, Kim J, Schneider C, Jacobson C, Molgó J, Stutzmann GE. Early presynaptic and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer’s disease mice. J Neurosci  2012; 32(24): 8341-53.
[http://dx.doi.org/10.1523/JNEUROSCI.0936-12.2012] [PMID: 22699914] 
[68] 
Goussakov I, Miller MB, Stutzmann GE. NMDA-mediated Ca(2+) influx drives aberrant ryanodine receptor activation in dendrites of young Alzheimer’s disease mice. J Neurosci  2010; 30(36): 12128-37.
[http://dx.doi.org/10.1523/JNEUROSCI.2474-10.2010] [PMID: 20826675] 
[69] 
Del Prete D, Checler F, Chami M. Ryanodine receptors: Physiological function and deregulation in Alzheimer disease. Mol Neurodegener  2014; 9: 21-1.
[http://dx.doi.org/10.1186/1750-1326-9-21] [PMID: 24902695] 
[70] 
Chakroborty S, Goussakov I, Miller MB, Stutzmann GE. Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3xTg-AD mice. J Neurosci  2009; 29(30): 9458-70.
[http://dx.doi.org/10.1523/JNEUROSCI.2047-09.2009] [PMID: 19641109] 
[71] 
Chan SL, Mayne M, Holden CP, Geiger JD, Mattson MP. Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J Biol Chem  2000; 275(24): 18195-200.
[http://dx.doi.org/10.1074/jbc.M000040200] [PMID: 10764737] 
[72] 
Payne AJ, Kaja S, Koulen P. Regulation of ryanodine receptor-mediated calcium signaling by presenilins. Receptors Clin Investig  2015; 2(1)e449
[PMID: 25646163] 
[73] 
Rybalchenko V, Hwang SY, Rybalchenko N, Koulen P. The cytosolic N-terminus of presenilin-1 potentiates mouse ryanodine receptor single channel activity. Int J Biochem Cell Biol  2008; 40(1): 84-97.
[PMID: 17709274] 
[74] 
Hayrapetyan V, Rybalchenko V, Rybalchenko N, Koulen P. The N-terminus of presenilin-2 increases single channel activity of brain ryanodine receptors through direct protein-protein interaction. Cell Calcium  2008; 44(5): 507-18.
[http://dx.doi.org/10.1016/j.ceca.2008.03.004] [PMID: 18440065] 
[75] 
Wu B, Yamaguchi H, Lai FA, Shen J. Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons. Proc Natl Acad Sci USA  2013; 110(37): 15091-6.
[http://dx.doi.org/10.1073/pnas.1304171110] [PMID: 23918386] 
[76] 
Leissring MA, Murphy MP, Mead TR, et al. A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP. Proc Natl Acad Sci USA  2002; 99(7): 4697-702.
[http://dx.doi.org/10.1073/pnas.072033799] [PMID: 11917117] 
[77] 
Niu Y, Su Z, Zhao C, et al. Effect of amyloid beta on capacitive calcium entry in neural 2a cells. Brain Res Bull  2009; 78(4-5): 152-7.
[http://dx.doi.org/10.1016/j.brainresbull.2008.10.003] [PMID: 19000747] 
[78] 
Oulès B, Del Prete D, Greco B, et al. Ryanodine receptor blockade reduces amyloid-β load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci  2012; 32(34): 11820-34.
[http://dx.doi.org/10.1523/JNEUROSCI.0875-12.2012] [PMID: 22915123] 
[79] 
Supnet C, Grant J, Kong H, Westaway D, Mayne M. Amyloid-beta-(1-42) increases ryanodine receptor-3 expression and function in neurons of TgCRND8 mice. J Biol Chem  2006; 281(50): 38440-7.
[http://dx.doi.org/10.1074/jbc.M606736200] [PMID: 17050533] 
[80] 
Paula-Lima AC, Hidalgo C. Amyloid β-peptide oligomers, ryanodine receptor-mediated Ca(2+) release, and Wnt-5a/Ca(2+) signaling: Opposing roles in neuronal mitochondrial dynamics? Front Cell Neurosci  2013; 7: 120.
[http://dx.doi.org/10.3389/fncel.2013.00120] [PMID: 23908603] 
[81] 
Giannini G, Conti A, Mammarella S, Scrobogna M, Sorrentino V. The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. J Cell Biol  1995; 128(5): 893-904.
[PMID: 7876312] 
[82] 
Chakroborty S, Briggs C, Miller MB, et al. Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer’s disease. PLoS One  2012; 7(12)e52056
[http://dx.doi.org/10.1371/journal.pone.0052056] [PMID: 23284867] 
[83] 
Peng J, Liang G, Inan S, et al. Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett  2012; 516(2): 274-9.
[http://dx.doi.org/10.1016/j.neulet.2012.04.008] [PMID: 22516463] 
[84] 
Zhang H, Sun S, Herreman A, De Strooper B, Bezprozvanny I. Role of presenilins in neuronal calcium homeostasis. J Neurosci  2010; 30(25): 8566-80.
[http://dx.doi.org/10.1523/JNEUROSCI.1554-10.2010] [PMID: 20573903] 
[85] 
Zhao X, Weisleder N, Han X, et al. Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor. J Biol Chem  2006; 281(44): 33477-86.
[http://dx.doi.org/10.1074/jbc.M602306200] [PMID: 16945924] 
[86] 
Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F. Dantrolene--a review of its pharmacology, therapeutic use and new developments. Anaesthesia  2004; 59(4): 364-73.
[http://dx.doi.org/10.1111/j.1365-2044.2004.03658.x] [PMID: 15023108] 
[87] 
Liang L, Wei H. Dantrolene, a treatment for Alzheimer disease? Alzheimer Dis Assoc Disord  2015; 29(1): 1-5.
[http://dx.doi.org/10.1097/WAD.0000000000000076] [PMID: 25551862] 
[88] 
Kushnir A, Marks AR. Ryanodine receptor patents. Recent Pat Biotechnol  2012; 6(3): 157-66.
[http://dx.doi.org/10.2174/1872208311206030157] [PMID: 23092431] 
[89] 
Lehnart SE, Mongillo M, Bellinger A, et al. Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. J Clin Invest  2008; 118(6): 2230-45.
[http://dx.doi.org/10.1172/JCI35346] [PMID: 18483626] 
[90] 
Lacampagne A, Liu X, Reiken S, et al. Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits. Acta Neuropathol  2017; 134(5): 749-67.
[http://dx.doi.org/10.1007/s00401-017-1733-7] [PMID: 28631094] 
[91] 
Cheung KH, Shineman D, Müller M, et al. Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron  2008; 58(6): 871-83.
[http://dx.doi.org/10.1016/j.neuron.2008.04.015] [PMID: 18579078] 
[92] 
Cheung KH, Mei L, Mak DO, et al. Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer’s disease-linked presenilin mutants in human cells and mouse neurons. Sci Signal  2010; 3(114): ra22.
[http://dx.doi.org/10.1126/scisignal.2000818] [PMID: 20332427] 
[93] 
Shilling D, Müller M, Takano H, et al. Suppression of InsP3 receptor-mediated Ca2+ signaling alleviates mutant presenilin-linked familial Alzheimer’s disease pathogenesis. J Neurosci  2014; 34(20): 6910-23.
[http://dx.doi.org/10.1523/JNEUROSCI.5441-13.2014] [PMID: 24828645] 
[94] 
Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee S-F, Hao YH, et al. Presenilins form ER calcium leak channels, a function disrupted by mutations linked to familial Alzheimer’s disease. Cell  2006; 126: 981-93.
[http://dx.doi.org/10.1016/j.cell.2006.06.059] [PMID: 16959576] 
[95] 
Nelson O, Tu H, Lei T, Bentahir M, de Strooper B, Bezprozvanny I. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest  2007; 117(5): 1230-9.
[http://dx.doi.org/10.1172/JCI30447] [PMID: 17431506] 
[96] 
Greotti E, Capitanio P, Wong A, Pozzan T, Pizzo P, Pendin D. Familial Alzheimer’s disease-linked presenilin mutants and intracellular Ca2+ handling: A single-organelle, FRET-based analysis. Cell Calcium  2019; 79: 44-56.
[http://dx.doi.org/10.1016/j.ceca.2019.02.005] [PMID: 30822648] 
[97] 
Nelson O, Supnet C, Tolia A, Horré K, De Strooper B, Bezprozvanny I. Mutagenesis mapping of the presenilin 1 calcium leak conductance pore. J Biol Chem  2011; 286(25): 22339-47.
[http://dx.doi.org/10.1074/jbc.M111.243063] [PMID: 21531718] 
[98] 
Li X, Dang S, Yan C, Gong X, Wang J, Shi Y. Structure of a presenilin family intramembrane aspartate protease. Nature  2013; 493(7430): 56-61.
[http://dx.doi.org/10.1038/nature11801] [PMID: 23254940] 
[99] 
Bai XC, Yan C, Yang G, et al. An atomic structure of human γ-secretase. Nature  2015; 525(7568): 212-7.
[http://dx.doi.org/10.1038/nature14892] [PMID: 26280335] 
[100] 
Nelson O, Supnet C, Liu H, Bezprozvanny I. Familial Alzheimer’s disease mutations in presenilins: Effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes. J Alzheimers Dis  2010; 21(3): 781-93.
[http://dx.doi.org/10.3233/JAD-2010-100159] [PMID: 20634584] 
[101] 
Putney JW Jr. Capacitative calcium entry in the nervous system. Cell Calcium  2003; 34(4-5): 339-44.
[http://dx.doi.org/10.1016/S0143-4160(03)00143-X] [PMID: 12909080] 
[102] 
Leissring MA, Akbari Y, Fanger CM, Cahalan MD, Mattson MP, LaFerla FM. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol  2000; 149(4): 793-8.
[http://dx.doi.org/10.1083/jcb.149.4.793] [PMID: 10811821] 
[103] 
Yoo AS, Cheng I, Chung S, et al. Presenilin-mediated modulation of capacitative calcium entry. Neuron  2000; 27(3): 561-72.
[http://dx.doi.org/10.1016/S0896-6273(00)00066-0] [PMID: 11055438] 
[104] 
Herms J, Schneider I, Dewachter I, Caluwaerts N, Kretzschmar H, Van Leuven F. Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein. J Biol Chem  2003; 278(4): 2484-9.
[http://dx.doi.org/10.1074/jbc.M206769200] [PMID: 12431992] 
[105] 
Baba A, Yasui T, Fujisawa S, et al. Activity-evoked capacitative Ca2+ entry: Implications in synaptic plasticity. J Neurosci  2003; 23(21): 7737-41.
[http://dx.doi.org/10.1523/JNEUROSCI.23-21-07737.2003] [PMID: 12944501] 
[106] 
Sun S, Zhang H, Liu J, et al. Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron  2014; 82(1): 79-93.
[http://dx.doi.org/10.1016/j.neuron.2014.02.019] [PMID: 24698269] 
[107] 
Popugaeva E, Pchitskaya E, Speshilova A, et al. STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity. Mol Neurodegener  2015; 10(1): 37.
[http://dx.doi.org/10.1186/s13024-015-0034-7] [PMID: 26275606] 
[108] 
Zhang H, Liu J, Sun S, Pchitskaya E, Popugaeva E, Bezprozvanny I. Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer’s disease. J Alzheimers Dis  2015; 45(2): 561-80.
[http://dx.doi.org/10.3233/JAD-142427] [PMID: 25589721] 
[109] 
Berna-Erro A, Braun A, Kraft R, et al. STIM2 regulates capacitive Ca2+ entry in neurons and plays a key role in hypoxic neuronal cell death. Sci Signal  2009; 2(93): ra67.
[http://dx.doi.org/10.1126/scisignal.2000522] [PMID: 19843959] 
[110] 
Gruszczynska-Biegala J, Kuznicki J. Native STIM2 and ORAI1 proteins form a calcium-sensitive and thapsigargin-insensitive complex in cortical neurons. J Neurochem  2013; 126(6): 727-38.
[http://dx.doi.org/10.1111/jnc.12320] [PMID: 23711249] 
[111] 
Korkotian E, Oni-Biton E, Segal M. The role of the store-operated calcium entry channel Orai1 in cultured rat hippocampal synapse formation and plasticity. J Physiol  2017; 595(1): 125-40.
[http://dx.doi.org/10.1113/JP272645] [PMID: 27393042] 
[112] 
Brandman O, Liou J, Park WS, Meyer T. STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell  2007; 131(7): 1327-39.
[http://dx.doi.org/10.1016/j.cell.2007.11.039] [PMID: 18160041] 
[113] 
Zhou Y, Mancarella S, Wang Y, et al. The short N-terminal domains of STIM1 and STIM2 control the activation kinetics of Orai1 channels. J Biol Chem  2009; 284(29): 19164-8.
[http://dx.doi.org/10.1074/jbc.C109.010900] [PMID: 19487696] 
[114] 
Darbellay B, Arnaudeau S, Ceroni D, Bader CR, Konig S, Bernheim L. Human muscle economy myoblast differentiation and excitation-contraction coupling use the same molecular partners, STIM1 and STIM2. J Biol Chem  2010; 285(29): 22437-47.
[http://dx.doi.org/10.1074/jbc.M110.118984] [PMID: 20436167] 
[115] 
Gruszczynska-Biegala J, Pomorski P, Wisniewska MB, Kuznicki J. Differential roles for STIM1 and STIM2 in store-operated calcium entry in rat neurons. PLoS One  2011; 6(4)e19285
[http://dx.doi.org/10.1371/journal.pone.0019285] [PMID: 21541286] 
[116] 
Liou J, Kim ML, Heo WD, et al. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol  2005; 15(13): 1235-41.
[http://dx.doi.org/10.1016/j.cub.2005.05.055] [PMID: 16005298] 
[117] 
Zhang SL, Yu Y, Roos J, et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature  2005; 437(7060): 902-5.
[http://dx.doi.org/10.1038/nature04147] [PMID: 16208375] 
[118] 
Peinelt C, Vig M, Koomoa DL, et al. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol  2006; 8(7): 771-3.
[http://dx.doi.org/10.1038/ncb1435] [PMID: 16733527] 
[119] 
Soboloff J, Spassova MA, Tang XD, Hewavitharana T, Xu W, Gill DL. Orai1 and STIM reconstitute store-operated calcium channel function. J Biol Chem  2006; 281(30): 20661-5.
[http://dx.doi.org/10.1074/jbc.C600126200] [PMID: 16766533] 
[120] 
Stathopulos PB, Li GY, Plevin MJ, Ames JB, Ikura M. Stored Ca2+ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: An initiation mechanism for capacitive Ca2+ entry. J Biol Chem  2006; 281(47): 35855-62.
[http://dx.doi.org/10.1074/jbc.M608247200] [PMID: 17020874] 
[121] 
Xu P, Lu J, Li Z, Yu X, Chen L, Xu T. Aggregation of STIM1 underneath the plasma membrane induces clustering of Orai1. Biochem Biophys Res Commun  2006; 350(4): 969-76.
[http://dx.doi.org/10.1016/j.bbrc.2006.09.134] [PMID: 17045966] 
[122] 
Hoover PJ, Lewis RS. Stoichiometric requirements for trapping and gating of Ca2+ release-activated Ca2+ (CRAC) channels by stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci USA  2011; 108(32): 13299-304.
[http://dx.doi.org/10.1073/pnas.1101664108] [PMID: 21788510] 
[123] 
Li Z, Liu L, Deng Y, et al. Graded activation of CRAC channel by binding of different numbers of STIM1 to Orai1 subunits. Cell Res  2011; 21(2): 305-15.
[http://dx.doi.org/10.1038/cr.2010.131] [PMID: 20838418] 
[124] 
He J, Yu T, Pan J, Li H. Visualisation and identification of the interaction between STIM1s in resting cells. PLoS One  2012; 7(3)e33377
[http://dx.doi.org/10.1371/journal.pone.0033377] [PMID: 22438918] 
[125] 
Balasuriya D, Srivats S, Murrell-Lagnado RD, Edwardson JM. Atomic force microscopy (AFM) imaging suggests that stromal interaction molecule 1 (STIM1) binds to Orai1 with sixfold symmetry. FEBS Lett  2014; 588(17): 2874-80.
[http://dx.doi.org/10.1016/j.febslet.2014.06.054] [PMID: 24996186] 
[126] 
Klejman ME, Gruszczynska-Biegala J, Skibinska-Kijek A, et al. Expression of STIM1 in brain and puncta-like co-localization of STIM1 and ORAI1 upon depletion of Ca(2+) store in neurons. Neurochem Int  2009; 54(1): 49-55.
[http://dx.doi.org/10.1016/j.neuint.2008.10.005] [PMID: 19013491] 
[127] 
Vlachos A, Korkotian E, Schonfeld E, Copanaki E, Deller T, Segal M. Synaptopodin regulates plasticity of dendritic spines in hippocampal neurons. J Neurosci  2009; 29(4): 1017-33.
[http://dx.doi.org/10.1523/JNEUROSCI.5528-08.2009] [PMID: 19176811] 
[128] 
Ng AN, Krogh M, Toresson H. Dendritic EGFP-STIM1 activation after type I metabotropic glutamate and muscarinic acetylcholine receptor stimulation in hippocampal neuron. J Neurosci Res  2011; 89(8): 1235-44.
[http://dx.doi.org/10.1002/jnr.22648] [PMID: 21538465] 
[129] 
Kyung T, Lee S, Kim JE, et al. Optogenetic control of endogenous Ca(2+) channels in vivo. Nat Biotechnol  2015; 33(10): 1092-6.
[http://dx.doi.org/10.1038/nbt.3350] [PMID: 26368050] 
[130] 
Majewski Ł, Maciąg F, Boguszewski PM, et al. Overexpression of STIM1 in neurons in mouse brain improves contextual learning and impairs long-term depression. Biochim Biophys Acta Mol Cell Res  2017; 1864(6): 1071-87.
[http://dx.doi.org/10.1016/j.bbamcr.2016.11.025] [PMID: 27913207] 
[131] 
Garcia-Alvarez G, Shetty MS, Lu B, et al. Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes. Front Behav Neurosci  2015; 9: 180.
[http://dx.doi.org/10.3389/fnbeh.2015.00180] [PMID: 26236206] 
[132] 
Tong BC, Lee CS, Cheng WH, Lai KO, Foskett JK, Cheung KH. Familial Alzheimer’s disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry. Sci Signal  2016; 9(444): ra89.
[http://dx.doi.org/10.1126/scisignal.aaf1371] [PMID: 27601731] 
[133] 
Zhang H, Sun S, Wu L, et al. Store-Operated calcium channel complex in postsynaptic spines: a new therapeutic target for Alzheimer’s disease treatment. J Neurosci  2016; 36(47): 11837-50.
[http://dx.doi.org/10.1523/JNEUROSCI.1188-16.2016] [PMID: 27881772] 
[134] 
Bojarski L, Pomorski P, Szybinska A, et al. Presenilin-dependent expression of STIM proteins and dysregulation of capacitative Ca2+ entry in familial Alzheimer’s disease. Biochim Biophys Acta  2009; 1793(6): 1050-7.
[http://dx.doi.org/10.1016/j.bbamcr.2008.11.008] [PMID: 19111578] 
[135] 
Garcia-Alvarez G, Lu B, Yap KA, et al. STIM2 regulates PKA-dependent phosphorylation and trafficking of AMPARs. Mol Biol Cell  2015; 26(6): 1141-59.
[http://dx.doi.org/10.1091/mbc.E14-07-1222] [PMID: 25609091] 
[136] 
Yap KA, Shetty MS, Garcia-Alvarez G, et al. STIM2 regulates AMPA receptor trafficking and plasticity at hippocampal synapses. Neurobiol Learn Mem  2017; 138: 54-61.
[PMID: 27544849] 
[137] 
Popugaeva E, Chernyuk D, Zhang H, et al. Derivatives of piperazines as potential therapeutic agents for Alzheimer’s disease. Mol Pharmacol  2019; 95(4): 337-48.
[http://dx.doi.org/10.1124/mol.118.114348] [PMID: 30696719] 
[138] 
Cheng KT, Ong HL, Liu X, Ambudkar IS. Contribution of TRPC1 and Orai1 to Ca(2+) entry activated by store depletion. Adv Exp Med Biol  2011; 704: 435-49.
[http://dx.doi.org/10.1007/978-94-007-0265-3_24] [PMID: 21290310] 
[139] 
Wu J, Shih HP, Vigont V, et al. Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington’s disease treatment. Chem Biol  2011; 18(6): 777-93.
[http://dx.doi.org/10.1016/j.chembiol.2011.04.012] [PMID: 21700213] 
[140] 
Linde CI, Baryshnikov SG, Mazzocco-Spezzia A, Golovina VA. Dysregulation of Ca2+ signaling in astrocytes from mice lacking amyloid precursor protein. Am J Physiol Cell Physiol  2011; 300(6): C1502-12.
[http://dx.doi.org/10.1152/ajpcell.00379.2010] [PMID: 21368296] 
[141] 
Ronco V, Grolla AA, Glasnov TN, et al. Differential deregulation of astrocytic calcium signalling by amyloid-β, TNFα, IL-1β and LPS. Cell Calcium  2014; 55(4): 219-29.
[http://dx.doi.org/10.1016/j.ceca.2014.02.016] [PMID: 24656753] 
[142] 
Alkhani H, Ase AR, Grant R, O’Donnell D, Groschner K, Séguéla P. Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors. Mol Pain  2014; 10: 43.
[http://dx.doi.org/10.1186/1744-8069-10-43] [PMID: 24965271] 
[143] 
Ong HL, de Souza LB, Ambudkar IS. Role of TRPC channels in store-operated calcium entry Calcium entry pathways in non-excitable cells.  Springer 2016; pp. 87-109.
[http://dx.doi.org/10.1007/978-3-319-26974-0_5] 
[144] 
Neuner SM, Wilmott LA, Hope KA, et al. TRPC3 channels critically regulate hippocampal excitability and contextual fear memory. Behav Brain Res  2015; 281: 69-77.
[http://dx.doi.org/10.1016/j.bbr.2014.12.018] [PMID: 25513972] 
[145] 
Zhou J, Du W, Zhou K, et al. Critical role of TRPC6 channels in the formation of excitatory synapses. Nat Neurosci  2008; 11(7): 741-3.
[http://dx.doi.org/10.1038/nn.2127] [PMID: 18516035] 
[146] 
Wang J, Lu R, Yang J, et al. TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production. Nat Commun  2015; 6: 8876.
[http://dx.doi.org/10.1038/ncomms9876] [PMID: 26581893] 
[147] 
Lessard CB, Lussier MP, Cayouette S, Bourque G, Boulay G. The overexpression of presenilin2 and Alzheimer’s-disease-linked presenilin2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells. Cell Signal  2005; 17(4): 437-45.
[http://dx.doi.org/10.1016/j.cellsig.2004.09.005] [PMID: 15601622] 
[148] 
Liao Y, Erxleben C, Yildirim E, Abramowitz J, Armstrong DL, Birnbaumer L. Orai proteins interact with TRPC channels and confer responsiveness to store depletion. Proc Natl Acad Sci USA  2007; 104(11): 4682-7.
[http://dx.doi.org/10.1073/pnas.0611692104] [PMID: 17360584] 
[149] 
Lu R, Wang J, Tao R, et al. Reduced TRPC6 mRNA levels in the blood cells of patients with Alzheimer’s disease and mild cognitive impairment. Mol Psychiatry  2018; 23(3): 767-76.
[http://dx.doi.org/10.1038/mp.2017.136] [PMID: 28696436] 
[150] 
Leuner K, Kazanski V, Müller M, et al. Hyperforin--a key constituent of St. John’s wort specifically activates TRPC6 channels. FASEB J  2007; 21(14): 4101-11.
[http://dx.doi.org/10.1096/fj.07-8110com] [PMID: 17666455] 
[151] 
Inestrosa NC, Tapia-Rojas C, Griffith TN, et al. Tetrahydrohyperforin prevents cognitive deficit, Aβ deposition, tau phosphorylation and synaptotoxicity in the APPswe/PSEN1ΔE9 model of Alzheimer’s disease: A possible effect on APP processing. Transl Psychiatry  2011; 1(7)e20
[http://dx.doi.org/10.1038/tp.2011.19] [PMID: 22832522] 
[152] 
Abbott AC, Calderon Toledo C, Aranguiz FC, Inestrosa NC, Varela-Nallar L. Tetrahydrohyperforin increases adult hippocampal neurogenesis in wild-type and APPswe/PS1ΔE9 mice. J Alzheimers Dis  2013; 34(4): 873-85.
[http://dx.doi.org/10.3233/JAD-121714] [PMID: 23302657] 
[153] 
Cerpa W, Hancke JL, Morazzoni P, et al. The hyperforin derivative IDN5706 occludes spatial memory impairments and neuropathological changes in a double transgenic Alzheimer’s mouse model. Curr Alzheimer Res  2010; 7(2): 126-33.
[http://dx.doi.org/10.2174/156720510790691218] [PMID: 19939230] 
[154] 
Dinamarca MC, Cerpa W, Garrido J, Hancke JL, Inestrosa NC. Hyperforin prevents beta-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer’s amyloid-beta-deposits. Mol Psychiatry  2006; 11(11): 1032-48.
[http://dx.doi.org/10.1038/sj.mp.4001866] [PMID: 16880827] 
[155] 
Gibon J, Deloulme JC, Chevallier T, Ladevèze E, Abrous DN, Bouron A. The antidepressant hyperforin increases the phosphorylation of CREB and the expression of TrkB in a tissue-specific manner. Int J Neuropsychopharmacol  2013; 16(1): 189-98.
[http://dx.doi.org/10.1017/S146114571100188X] [PMID: 22226089] 
[156] 
Heiser JH, Schuwald AM, Sillani G, Ye L, Müller WE, Leuner K. TRPC6 channel-mediated neurite outgrowth in PC12 cells and hippocampal neurons involves activation of RAS/MEK/ERK, PI3K, and CAMKIV signaling. J Neurochem  2013; 127(3): 303-13.
[http://dx.doi.org/10.1111/jnc.12376] [PMID: 23875811] 
[157] 
Zolezzi JM, Carvajal FJ, Ríos JA, et al. Tetrahydrohyperforin induces mitochondrial dynamics and prevents mitochondrial Ca2+ overload after Aβ and Aβ-AChE complex challenge in rat hippocampal neurons. J Alzheimers Dis  2013; 37(4): 735-46.
[http://dx.doi.org/10.3233/JAD-130173] [PMID: 23948911] 
[158] 
Ting CP, Maimone TJ. Total Synthesis of Hyperforin. J Am Chem Soc  2015; 137(33): 10516-9.
[http://dx.doi.org/10.1021/jacs.5b06939] [PMID: 26252484] 
[159] 
Di Carlo G, Borrelli F, Ernst E, Izzo AA. St John’s wort: Prozac from the plant kingdom. Trends Pharmacol Sci  2001; 22(6): 292-7.
[http://dx.doi.org/10.1016/S0165-6147(00)01716-8] [PMID: 11395157] 
[160] 
Woelk H, Burkard G, Grünwald J. Benefits and risks of the hypericum extract LI 160: Drug monitoring study with 3250 patients. J Geriatr Psychiatry Neurol  1994; 7(1): S34-8.
[http://dx.doi.org/10.1177/089198879400701s10] [PMID: 7857506] 
[161] 
Popugaeva E, Pchitskaya E, Bezprozvanny I. Dysregulation of neuronal calcium homeostasis in Alzheimer’s disease - a therapeutic opportunity? Biochem Biophys Res Commun  2017; 483(4): 998-1004.
[http://dx.doi.org/10.1016/j.bbrc.2016.09.053] [PMID: 27641664] 
[162] 
Chernyuk D, Zernov N, Kabirova M, Bezprozvanny I, Popugaeva E. Antagonist of neuronal store-operated calcium entry exerts beneficial effects in neurons expressing PSEN1ΔE9 mutant linked to familial Alzheimer disease. Neuroscience  2019; 410: 118-27.
[PMID: 31055008] 
Cite As
Current Alzheimer Research

Reversal of Calcium Dysregulation as Potential Approach for Treating Alzheimer's Disease

Abstract
