Dangerous Liaisons: Tau Interaction with Muscarinic Receptors

doi:10.2174/1567205017666200424134311
摘要

神经退行性疾病（例如阿尔茨海默氏病-AD）的分子过程仍然知之甚少。还迫切需要AD中的疾病改善疗法，因为本发明的治疗方法乙酰胆碱酯酶抑制剂和NMDA拮抗剂不能阻止其进展。 AD和其他痴呆症表现出独特的病理学特征，例如微管相关蛋白tau代谢调节。 Tau具有许多结合伴侣，包括信号分子，细胞骨架成分和脂质，这表明它是一种多功能蛋白质。 AD还与脑中胆碱能标志物的严重丧失有关，并且这种丧失可能是由于tau与胆碱能毒蕈碱受体的毒性相互作用。通过使用毒蕈碱受体的特异性拮抗剂，在体外发现胞外tau与M1和M3受体结合，并且在tau结合后神经元细胞中发现胞内钙的增加。然而，到目前为止，在陶氏病模型中通过毒蕈碱受体体内tau信号传导的重要性仍不确定。本文审查的数据突出了M1受体/ tau相互作用在加重与tauopathy相关的病理特征方面的显著作用，并表明选择性M1激动剂可作为未来治疗发展的原型，以朝着目前顽固的神经退行性疾病（如tauopathies）的修饰发展。
关键词: Tau，tauopathies，神经退行性疾病，毒蕈碱受体，胆碱能系统，审查。
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[1] 
Mandelkow E-M, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med  2012; 2(7)a006247
[http://dx.doi.org/10.1101/cshperspect.a006247] [PMID: 22762014] 
[2] 
Lee VM-Y, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci  2001; 24(1): 1121-59.
[http://dx.doi.org/10.1146/annurev.neuro.24.1.1121] [PMID: 11520930] 
[3] 
Ballatore C, Lee VM-Y, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci  2007; 8(9): 663-72.
[http://dx.doi.org/10.1038/nrn2194] [PMID: 17684513] 
[4] 
Goedert M, Falcon B, Clavaguera F, Tolnay M. Prion-like mechanisms in the pathogenesis of tauopathies and synucleinopathies. Curr Neurol Neurosci Rep  2014; 14(11): 495.
[http://dx.doi.org/10.1007/s11910-014-0495-z] [PMID: 25218483] 
[5] 
Saper CB, Wainer BH, German DC. Axonal and transneuronal transport in the transmission of neurological disease: potential role in system degenerations, including Alzheimer’s disease. Neuroscience  1987; 23(2): 389-98.
[http://dx.doi.org/10.1016/0306-4522(87)90063-7] [PMID: 2449630] 
[6] 
Fukutani Y, Kobayashi K, Nakamura I, Watanabe K, Isaki K, Cairns NJ. Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer’s disease. Neurosci Lett  1995; 200(1): 57-60.
[http://dx.doi.org/10.1016/0304-3940(95)12083-G] [PMID: 8584267] 
[7] 
de Calignon A, Polydoro M, Suárez-Calvet M, et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron  2012; 73(4): 685-97.
[http://dx.doi.org/10.1016/j.neuron.2011.11.033] [PMID: 22365544] 
[8] 
Liu L, Drouet V, Wu JW, et al. Trans-synaptic spread of tau pathology in vivo. PLoS One  2012; 7(2)e31302
[http://dx.doi.org/10.1371/journal.pone.0031302] [PMID: 22312444] 
[9] 
Bradley SJ, Bourgognon J-M, Sanger HE, et al. M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. J Clin Invest  2017; 127(2): 487-99.
[http://dx.doi.org/10.1172/JCI87526] [PMID: 27991860] 
[10] 
Pooler AM, Phillips EC, Lau DHW, Noble W, Hanger DP. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep  2013; 14(4): 389-94.
[http://dx.doi.org/10.1038/embor.2013.15] [PMID: 23412472] 
[11] 
Kanmert D, Cantlon A, Muratore CR, et al. C-terminally truncated forms of tau, but not full-length tau or its c-terminal fragments, are released from neurons independently of cell death. J Neurosci  2015; 35(30): 10851-65.
[http://dx.doi.org/10.1523/JNEUROSCI.0387-15.2015] [PMID: 26224867] 
[12] 
Simón D, García-García E, Royo F, Falcón-Pérez JM, Avila J. Proteostasis of tau. Tau overexpression results in its secretion via membrane vesicles. FEBS Lett  2012; 586(1): 47-54.
[http://dx.doi.org/10.1016/j.febslet.2011.11.022] [PMID: 22138183] 
[13] 
Yamada K, Holth JK, Liao F, et al. Neuronal activity regulates extracellular tau in vivo. J Exp Med  2014; 211(3): 387-93.
[http://dx.doi.org/10.1084/jem.20131685] [PMID: 24534188] 
[14] 
Saman S, Kim W, Raya M, et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem  2012; 287(6): 3842-9.
[http://dx.doi.org/10.1074/jbc.M111.277061] [PMID: 22057275] 
[15] 
Wu JW, Herman M, Liu L, et al. Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem  2013; 288(3): 1856-70.
[http://dx.doi.org/10.1074/jbc.M112.394528] [PMID: 23188818] 
[16] 
Evans LD, Wassmer T, Fraser G, et al. Extracellular monomeric and aggregated tau efficiently enter human neurons through overlapping but distinct pathways. Cell Rep  2018; 22(13): 3612-24.
[http://dx.doi.org/10.1016/j.celrep.2018.03.021] [PMID: 29590627] 
[17] 
Fuster-Matanzo A, Hernández F, Ávila J. Tau Spreading mechanisms; implications for dysfunctional tauopathies. Int J Mol Sci  2018; 19(3): 1-14.
[http://dx.doi.org/10.3390/ijms19030645] [PMID: 29495325] 
[18] 
Guix FX, Corbett GT, Cha DJ, et al. Detection of aggregation-competent tau in neuron-derived extracellular vesicles. Int J Mol Sci  2018; 19(3): 663.
[http://dx.doi.org/10.3390/ijms19030663] [PMID: 29495441] 
[19] 
Avila J, Simón D, Díaz-Hernández M, Pintor J, Hernández F. Sources of extracellular tau and its signaling. J Alzheimers Dis  2014; 40(S1): S7-S15.
[http://dx.doi.org/10.3233/JAD-131832] [PMID: 24531154] 
[20] 
Gómez-Ramos A, Díaz-Hernández M, Cuadros R, Hernández F, Avila J. Extracellular tau is toxic to neuronal cells. FEBS Lett  2006; 580(20): 4842-50.
[http://dx.doi.org/10.1016/j.febslet.2006.07.078] [PMID: 16914144] 
[21] 
Gómez-Ramos A, Díaz-Hernández M, Rubio A, Díaz-Hernández JI, Miras-Portugal MT, Avila J. Characteristics and consequences of muscarinic receptor activation by tau protein. Eur Neuropsychopharmacol  2009; 19(10): 708-17.
[http://dx.doi.org/10.1016/j.euroneuro.2009.04.006] [PMID: 19423301] 
[22] 
Zhang Y, Chen L, Shen G, Zhao Q, Shangguan L, He M. GRK5 dysfunction accelerates tau hyperphosphorylation in APP (swe) mice through impaired cholinergic activity. Neuroreport  2014; 25(7): 542-7.
[http://dx.doi.org/10.1097/WNR.0000000000000142] [PMID: 24598771] 
[23] 
Liu J, Rasul I, Sun Y, et al. GRK5 deficiency leads to reduced hippocampal acetylcholine level via impaired presynaptic M2/M4 autoreceptor desensitization. J Biol Chem  2009; 284(29): 19564-71.
[http://dx.doi.org/10.1074/jbc.M109.005959] [PMID: 19478075] 
[24] 
Zhang Y, Zhao J, Yin M, et al. The influence of two functional genetic variants of GRK5 on tau phosphorylation and their association with Alzheimer’s disease risk. Oncotarget  2017; 8(42): 72714-26.
[http://dx.doi.org/10.18632/oncotarget.20283] [PMID: 29069820] 
[25] 
Caccamo A, Fisher A, LaFerla FM. M1 agonists as a potential disease-modifying therapy for Alzheimer’s disease. Curr Alzheimer Res  2009; 6(2): 112-7.
[http://dx.doi.org/10.2174/156720509787602915] [PMID: 19355845] 
[26] 
Fisher A. Cholinergic modulation of amyloid precursor protein processing with emphasis on M1 muscarinic receptor: perspectives and challenges in treatment of Alzheimer’s disease. J Neurochem  2012; 120(1): 22-33.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07507.x] [PMID: 22122190] 
[27] 
Clader JW, Wang Y. Muscarinic receptor agonists and antagonists in the treatment of Alzheimer’s disease. Curr Pharm Des  2005; 11(26): 3353-61.
[http://dx.doi.org/10.2174/138161205774370762] [PMID: 16250841] 
[28] 
Fisher A. M1 muscarinic agonists target major hallmarks of Alzheimer’s disease--the pivotal role of brain M1 receptors. Neurodegener Dis  2008; 5(3-4): 237-40.
[http://dx.doi.org/10.1159/000113712] [PMID: 18322400] 
[29] 
Zhang F, Zhong R, Li S, et al. Acute hypoxia induced an imbalanced M1/M2 activation of nicroglia through NF-κB signaling in Alzheimer’s disease mice and wild-type littermates. Front Aging Neurosci  2017; 9: 282.
[http://dx.doi.org/10.3389/fnagi.2017.00282] [PMID: 28890695] 
[30] 
Medeiros R, Kitazawa M, Caccamo A, et al. Loss of muscarinic M1 receptor exacerbates Alzheimer’s disease-like pathology and cognitive decline. Am J Pathol  2011; 179(2): 980-91.
[http://dx.doi.org/10.1016/j.ajpath.2011.04.041] [PMID: 21704011] 
[31] 
Huber CM, Yee C, May T, Dhanala A, Mitchell CS. Cognitive decline in preclinical Alzheimer’s disease: Amyloid-beta versus tauopathy. J Alzheimers Dis  2018; 61(1): 265-81.
[http://dx.doi.org/10.3233/JAD-170490] [PMID: 29154274] 
[32] 
Nyakas C, Granic I, Halmy LG, Banerjee P, Luiten PGM. The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-β42 with memantine. Behav Brain Res  2011; 221(2): 594-603.
[http://dx.doi.org/10.1016/j.bbr.2010.05.033] [PMID: 20553766] 
[33] 
Liu F, Gong C-X. Tau exon 10 alternative splicing and tauopathies. Mol Neurodegener  2008; 3(1): 8.
[http://dx.doi.org/10.1186/1750-1326-3-8] [PMID: 18616804] 
[34] 
Fuster-Matanzo A, Llorens-Martín M, Jurado-Arjona J, Avila J, Hernández F. Tau protein and adult hippocampal neurogenesis. Front Neurosci  2012; 6: 104.
[http://dx.doi.org/10.3389/fnins.2012.00104] [PMID: 22787440] 
[35] 
Avila J, Lucas JJ, Pérez M, Hernández F. Role of tau protein in both physiological and pathological conditions. Physiol Rev  2004; 84(2): 361-84.
[http://dx.doi.org/10.1152/physrev.00024.2003] [PMID: 15044677] 
[36] 
Dotti CG, Banker GA, Binder LI. The expression and distribution of the microtubule-associated proteins tau and microtubule-associated protein 2 in hippocampal neurons in the rat in situ and in cell culture. Neuroscience  1987; 23(1): 121-30.
[http://dx.doi.org/10.1016/0306-4522(87)90276-4] [PMID: 3120034] 
[37] 
Kaech S, Banker G. Culturing hippocampal neurons. Nat Protoc  2006; 1(5): 2406-15.
[http://dx.doi.org/10.1038/nprot.2006.356] [PMID: 17406484] 
[38] 
Niewiadomska G, Baksalerska-Pazera M, Lenarcik I, Riedel G. Compartmental protein expression of Tau, GSK-3β and TrkA in cholinergic neurons of aged rats. J Neural Transm (Vienna)  2006; 113(11): 1733-46.
[http://dx.doi.org/10.1007/s00702-006-0488-4] [PMID: 16736240] 
[39] 
Ittner LM, Ke YD, Delerue F, et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer’s disease mouse models. Cell  2010; 142(3): 387-97.
[http://dx.doi.org/10.1016/j.cell.2010.06.036] [PMID: 20655099] 
[40] 
Brandt R, Léger J, Lee G. Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain. J Cell Biol  1995; 131(5): 1327-40.
[http://dx.doi.org/10.1083/jcb.131.5.1327] [PMID: 8522593] 
[41] 
Arrasate M, Pérez M, Avila J. Tau dephosphorylation at tau-1 site correlates with its association to cell membrane. Neurochem Res  2000; 25(1): 43-50.
[http://dx.doi.org/10.1023/A:1007583214722] [PMID: 10685603] 
[42] 
Sultan A, Nesslany F, Violet M, et al. Nuclear tau, a key player in neuronal DNA protection. J Biol Chem  2011; 286(6): 4566-75.
[http://dx.doi.org/10.1074/jbc.M110.199976] [PMID: 21131359] 
[43] 
Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow E-M. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol  2002; 156(6): 1051-63.
[http://dx.doi.org/10.1083/jcb.200108057] [PMID: 11901170] 
[44] 
Knops J, Kosik KS, Lee G, Pardee JD, Cohen-Gould L, McConlogue L. Overexpression of tau in a nonneuronal cell induces long cellular processes. J Cell Biol  1991; 114(4): 725-33.
[http://dx.doi.org/10.1083/jcb.114.4.725] [PMID: 1678391] 
[45] 
Frandemiche ML, De Seranno S, Rush T, et al. Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers. J Neurosci  2014; 34(17): 6084-97.
[http://dx.doi.org/10.1523/JNEUROSCI.4261-13.2014] [PMID: 24760868] 
[46] 
Violet M, Delattre L, Tardivel M, et al. A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front Cell Neurosci  2014; 8: 84.
[http://dx.doi.org/10.3389/fncel.2014.00084] [PMID: 24672431] 
[47] 
Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci  2016; 17(1): 5-21.
[http://dx.doi.org/10.1038/nrn.2015.1] [PMID: 26631930] 
[48] 
Martin L, Latypova X, Terro F. Post-translational modifications of tau protein: implications for Alzheimer’s disease. Neurochem Int  2011; 58(4): 458-71.
[http://dx.doi.org/10.1016/j.neuint.2010.12.023] [PMID: 21215781] 
[49] 
Sergeant N, Bretteville A, Hamdane M, et al. Biochemistry of Tau in Alzheimer’s disease and related neurological disorders. Expert Rev Proteomics  2008; 5(2): 207-24.
[http://dx.doi.org/10.1586/14789450.5.2.207] [PMID: 18466052] 
[50] 
Lin Y-T, Cheng J-T, Liang L-C, Ko C-Y, Lo Y-K, Lu P-J. The binding and phosphorylation of Thr231 is critical for Tau’s hyperphosphorylation and functional regulation by glycogen synthase kinase 3β. J Neurochem  2007; 103(2): 802-13.
[http://dx.doi.org/10.1111/j.1471-4159.2007.04792.x] [PMID: 17680984] 
[51] 
Jeganathan S, von Bergen M, Brutlach H, Steinhoff H-J, Mandelkow E. Global hairpin folding of tau in solution. Biochemistry  2006; 45(7): 2283-93.
[http://dx.doi.org/10.1021/bi0521543] [PMID: 16475817] 
[52] 
Jeganathan S, Hascher A, Chinnathambi S, Biernat J, Mandelkow E-M, Mandelkow E. Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC-1) conformation. J Biol Chem  2008; 283(46): 32066-76.
[http://dx.doi.org/10.1074/jbc.M805300200] [PMID: 18725412] 
[53] 
Rosseels J, Van den Brande J, Violet M, et al. Tau monoclonal antibody generation based on humanized yeast models: impact on Tau oligomerization and diagnostics. J Biol Chem  2015; 290(7): 4059-74.
[http://dx.doi.org/10.1074/jbc.M114.627919] [PMID: 25540200] 
[54] 
Kanaan NM, Morfini GA, LaPointe NE, et al. Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J Neurosci  2011; 31(27): 9858-68.
[http://dx.doi.org/10.1523/JNEUROSCI.0560-11.2011] [PMID: 21734277] 
[55] 
LaPointe NE, Morfini G, Pigino G, et al. The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. J Neurosci Res  2009; 87(2): 440-51.
[http://dx.doi.org/10.1002/jnr.21850] [PMID: 18798283] 
[56] 
Kanaan NM, Morfini G, Pigino G, et al. Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport. Neurobiol Aging  2012; 33(4): 826.e15-30.
[http://dx.doi.org/10.1016/j.neurobiolaging.2011.06.006] [PMID: 21794954] 
[57] 
Gamblin TC, Chen F, Zambrano A, et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci USA  2003; 100(17): 10032-7.
[http://dx.doi.org/10.1073/pnas.1630428100] [PMID: 12888622] 
[58] 
Medina M, Hernández F, Avila J. New features about tau function and dysfunction. Biomolecules  2016; 6(2): 21.
[http://dx.doi.org/10.3390/biom6020021] [PMID: 27104579] 
[59] 
Hoover BR, Reed MN, Su J, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron  2010; 68(6): 1067-81.
[http://dx.doi.org/10.1016/j.neuron.2010.11.030] [PMID: 21172610] 
[60] 
Zempel H, Thies E, Mandelkow E, Mandelkow E-M. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci  2010; 30(36): 11938-50.
[http://dx.doi.org/10.1523/JNEUROSCI.2357-10.2010] [PMID: 20826658] 
[61] 
Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA  1986; 83(13): 4913-7.
[http://dx.doi.org/10.1073/pnas.83.13.4913] [PMID: 3088567] 
[62] 
Ittner LM, Ke YD, Götz J. Phosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease. J Biol Chem  2009; 284(31): 20909-16.
[http://dx.doi.org/10.1074/jbc.M109.014472] [PMID: 19491104] 
[63] 
Min S-W, Chen X, Tracy TE, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med  2015; 21(10): 1154-62.
[http://dx.doi.org/10.1038/nm.3951] [PMID: 26390242] 
[64] 
Cook C, Carlomagno Y, Gendron TF, et al. Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance. Hum Mol Genet  2014; 23(1): 104-16.
[http://dx.doi.org/10.1093/hmg/ddt402] [PMID: 23962722] 
[65] 
David DC, Layfield R, Serpell L, Narain Y, Goedert M, Spillantini MG. Proteasomal degradation of tau protein. J Neurochem  2002; 83(1): 176-85.
[http://dx.doi.org/10.1046/j.1471-4159.2002.01137.x] [PMID: 12358741] 
[66] 
Grune T, Botzen D, Engels M, et al. Tau protein degradation is catalyzed by the ATP/ubiquitin-independent 20S proteasome under normal cell conditions. Arch Biochem Biophys  2010; 500(2): 181-8.
[http://dx.doi.org/10.1016/j.abb.2010.05.008] [PMID: 20478262] 
[67] 
Cripps D, Thomas SN, Jeng Y, Yang F, Davies P, Yang AJ. Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-Tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation. J Biol Chem  2006; 281(16): 10825-38.
[http://dx.doi.org/10.1074/jbc.M512786200] [PMID: 16443603] 
[68] 
Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Titani K, Ihara Y. Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments. Neuron  1993; 10(6): 1151-60.
[http://dx.doi.org/10.1016/0896-6273(93)90063-W] [PMID: 8391280] 
[69] 
Tan JMM, Wong ESP, Kirkpatrick DS, et al. Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases. Hum Mol Genet  2008; 17(3): 431-9.
[http://dx.doi.org/10.1093/hmg/ddm320] [PMID: 17981811] 
[70] 
Paine S, Bedford L, Thorpe JR, et al. Immunoreactivity to Lys63-linked polyubiquitin is a feature of neurodegeneration. Neurosci Lett  2009; 460(3): 205-8.
[http://dx.doi.org/10.1016/j.neulet.2009.05.074] [PMID: 19500650] 
[71] 
Keck S, Nitsch R, Grune T, Ullrich O. Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer’s disease. J Neurochem  2003; 85(1): 115-22.
[http://dx.doi.org/10.1046/j.1471-4159.2003.01642.x] [PMID: 12641733] 
[72] 
Del Pino J, Zeballos G, Anadón MJ, et al. Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3β enzyme, β-amyloid and tau protein levels. Arch Toxicol  2016; 90(5): 1081-92.
[http://dx.doi.org/10.1007/s00204-015-1540-7] [PMID: 26026611] 
[73] 
Keller JN, Hanni KB, Markesbery WR. Impaired proteasome function in Alzheimer’s disease. J Neurochem  2000; 75(1): 436-9.
[http://dx.doi.org/10.1046/j.1471-4159.2000.0750436.x] [PMID: 10854289] 
[74] 
Lopez Salon M, Pasquini L, Besio Moreno M, Pasquini JM, Soto E. Relationship between beta-amyloid degradation and the 26S proteasome in neural cells. Exp Neurol  2003; 180(2): 131-43.
[http://dx.doi.org/10.1016/S0014-4886(02)00060-2] [PMID: 12684027] 
[75] 
Gupta R, Lan M, Mojsilovic-Petrovic J, Choi WH, Safren N, Barmada S, et al. The proline/arginine dipeptide from hexanucleotide repeat expanded C9ORF72 inhibits the proteasome Neuro 2017. 4(1): ENEURO.0249-16.2017
[76] 
Shin ET, Joehlin-Price AS, Agnese DM, Zynger DL. Minimal clinical impact of intraoperative examination of sentinel lymph nodes in patients with ductal carcinoma in situ. Am J Clin Pathol  2017; 148(5): 374-9.
[http://dx.doi.org/10.1093/ajcp/aqx089] [PMID: 29016707] 
[77] 
Liu F, Zaidi T, Iqbal K, Grundke-Iqbal I, Gong C-X. Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5. Neuroscience  2002; 115(3): 829-37.
[http://dx.doi.org/10.1016/S0306-4522(02)00510-9] [PMID: 12435421] 
[78] 
Watanabe A, Hong W-K, Dohmae N, Takio K, Morishima-Kawashima M, Ihara Y. Molecular aging of tau: disulfide-independent aggregation and non-enzymatic degradation in vitro and in vivo. J Neurochem  2004; 90(6): 1302-11.
[http://dx.doi.org/10.1111/j.1471-4159.2004.02611.x] [PMID: 15341514] 
[79] 
Yan SD, Yan SF, Chen X, et al. Non-enzymatically glycated tau in Alzheimer’s disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med  1995; 1(7): 693-9.
[http://dx.doi.org/10.1038/nm0795-693] [PMID: 7585153] 
[80] 
Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong C-X. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci USA  2004; 101(29): 10804-9.
[http://dx.doi.org/10.1073/pnas.0400348101] [PMID: 15249677] 
[81] 
Yuzwa SA, Cheung AH, Okon M, McIntosh LP, Vocadlo DJ. O-GlcNAc modification of tau directly inhibits its aggregation without perturbing the conformational properties of tau monomers. J Mol Biol  2014; 426(8): 1736-52.
[http://dx.doi.org/10.1016/j.jmb.2014.01.004] [PMID: 24444746] 
[82] 
Babu JR, Geetha T, Wooten MW. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem  2005; 94(1): 192-203.
[http://dx.doi.org/10.1111/j.1471-4159.2005.03181.x] [PMID: 15953362] 
[83] 
Luo H-B, Xia Y-Y, Shu X-J, et al. SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc Natl Acad Sci USA  2014; 111(46): 16586-91.
[http://dx.doi.org/10.1073/pnas.1417548111] [PMID: 25378699] 
[84] 
Chai Y, Tian D, Yang Y, et al. Apoptotic regulators promote cytokinetic midbody degradation in C. elegans. J Cell Biol  2012; 199(7): 1047-55.
[http://dx.doi.org/10.1083/jcb.201209050] [PMID: 23253479] 
[85] 
Díaz-Hernández M, Gómez-Ramos A, Rubio A, et al. Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. J Biol Chem  2010; 285(42): 32539-48.
[http://dx.doi.org/10.1074/jbc.M110.145003] [PMID: 20634292] 
[86] 
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] 
[87] 
Barten DM, Fanara P, Andorfer C, et al. Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027. J Neurosci  2012; 32(21): 7137-45.
[http://dx.doi.org/10.1523/JNEUROSCI.0188-12.2012] [PMID: 22623658] 
[88] 
Yamada K, Cirrito JR, Stewart FR, et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci  2011; 31(37): 13110-7.
[http://dx.doi.org/10.1523/JNEUROSCI.2569-11.2011] [PMID: 21917794] 
[89] 
Bright J, Hussain S, Dang V, et al. Human secreted tau increases amyloid-beta production. Neurobiol Aging  2015; 36(2): 693-709.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.09.007] [PMID: 25442111] 
[90] 
Yamada K. Extracellular tau and its potential role in the propagation of tau pathology. Front Neurosci  2017; 11: 667.
[http://dx.doi.org/10.3389/fnins.2017.00667] [PMID: 29238289] 
[91] 
Gauthier-Kemper A, Weissmann C, Golovyashkina N, et al. The frontotemporal dementia mutation R406W blocks tau’s interaction with the membrane in an annexin A2-dependent manner. J Cell Biol  2011; 192(4): 647-61.
[http://dx.doi.org/10.1083/jcb.201007161] [PMID: 21339331] 
[92] 
Kalra H, Simpson RJ, Ji H, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol  2012; 10(12)e1001450
[http://dx.doi.org/10.1371/journal.pbio.1001450] [PMID: 23271954] 
[93] 
Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics  2010; 73(10): 1907-20.
[http://dx.doi.org/10.1016/j.jprot.2010.06.006] [PMID: 20601276] 
[94] 
Davizon P, Munday AD, López JA. Tissue factor, lipid rafts, and microparticles. Semin Thromb Hemost  2010; 36(8): 857-64.
[http://dx.doi.org/10.1055/s-0030-1267039] [PMID: 21049386] 
[95] 
Dujardin S, Bégard S, Caillierez R, et al. Ectosomes: a new mechanism for non-exosomal secretion of tau protein. PLoS One  2014; 9(6)e100760
[http://dx.doi.org/10.1371/journal.pone.0100760] [PMID: 24971751] 
[96] 
Fontaine SN, Zheng D, Sabbagh JJ, et al. DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins. EMBO J  2016; 35(14): 1537-49.
[http://dx.doi.org/10.15252/embj.201593489] [PMID: 27261198] 
[97] 
Rodriguez L, Mohamed N-V, Desjardins A, Lippé R, Fon EA, Leclerc N. Rab7A regulates tau secretion. J Neurochem  2017; 141(4): 592-605.
[http://dx.doi.org/10.1111/jnc.13994] [PMID: 28222213] 
[98] 
Mohamed NV, Desjardins A, Leclerc N. Tau secretion is correlated to an increase of Golgi dynamics. PLoS One  2017; 12(5)e0178288
[http://dx.doi.org/10.1371/journal.pone.0178288] [PMID: 28552936] 
[99] 
Rustom LE, Boudou T, Lou S, et al. Micropore-induced capillarity enhances bone distribution in vivo in biphasic calcium phosphate scaffolds. Acta Biomater  2016; 44: 144-54.
[http://dx.doi.org/10.1016/j.actbio.2016.08.025] [PMID: 27544807] 
[100] 
Rustom A, Saffrich R, Markovic I, Walther P, Gerdes H-H. Nanotubular highways for intercellular organelle transport Science (80- )  2004; 303(5660): 1007-.
[http://dx.doi.org/10.1126/science.1093133] 
[101] 
Tardivel M, Bégard S, Bousset L, et al. Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies. Acta Neuropathol Commun  2016; 4(1): 117.
[http://dx.doi.org/10.1186/s40478-016-0386-4] [PMID: 27809932] 
[102] 
Abounit S, Wu JW, Duff K, Victoria GS, Zurzolo C. Tunneling nanotubes: A possible highway in the spreading of tau and other prion-like proteins in neurodegenerative diseases. Prion  2016; 10(5): 344-51.
[http://dx.doi.org/10.1080/19336896.2016.1223003] [PMID: 27715442] 
[103] 
Karch CM, Jeng AT, Goate AM. Extracellular Tau levels are influenced by variability in Tau that is associated with tauopathies. J Biol Chem  2012; 287(51): 42751-62.
[http://dx.doi.org/10.1074/jbc.M112.380642] [PMID: 23105105] 
[104] 
Plouffe V, Mohamed N-V, Rivest-McGraw J, Bertrand J, Lauzon M, Leclerc N. Hyperphosphorylation and cleavage at D421 enhance tau secretion. PLoS One  2012; 7(5)e36873
[http://dx.doi.org/10.1371/journal.pone.0036873] [PMID: 22615831] 
[105] 
Mohamed N-V, Plouffe V, Rémillard-Labrosse G, Planel E, Leclerc N. Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons. Sci Rep  2014; 4(1): 5715.
[http://dx.doi.org/10.1038/srep05715] [PMID: 25030297] 
[106] 
Jiang S, Li Y, Zhang C. Zhao Y, Bu G, Xu H, et al.M1 muscarinic acetylcholine receptor in Alzheimer’s disease. Neurosci Bull  2014; 30(2): 295-307.
[107] 
Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev  1998; 50(2): 279-90.
[PMID: 9647869] 
[108] 
Felder CC, Bymaster FP, Ward J, DeLapp N. Therapeutic opportunities for muscarinic receptors in the central nervous system. J Med Chem  2000; 43(23): 4333-53.
[http://dx.doi.org/10.1021/jm990607u] [PMID: 11087557] 
[109] 
Matsui M, Yamada S, Oki T, Manabe T, Taketo MM, Ehlert FJ. Functional analysis of muscarinic acetylcholine receptors using knockout mice. Life Sci  2004; 75(25): 2971-81.
[http://dx.doi.org/10.1016/j.lfs.2004.05.034] [PMID: 15474550] 
[110] 
Puri V, Wang X, Vardigan JD, Kuduk SD, Uslaner JM. The selective positive allosteric M1 muscarinic receptor modulator PQCA attenuates learning and memory deficits in the Tg2576 Alzheimer’s disease mouse model. Behav Brain Res  2015; 287: 96-9.
[http://dx.doi.org/10.1016/j.bbr.2015.03.029] [PMID: 25800972] 
[111] 
Jakubík J, El-Fakahany EE. Allosteric modulation of muscarinic acetylcholine receptors. Pharmaceuticals (Basel)  2010; 3(9): 2838-60.
[http://dx.doi.org/10.3390/ph3092838] [PMID: 27713379] 
[112] 
Wess J. Allosteric binding sites on muscarinic acetylcholine receptors. Mol Pharmacol  2005; 68(6): 1506-9.
[http://dx.doi.org/10.1124/mol.105.019141] [PMID: 16183853] 
[113] 
Dencker D, Thomsen M, Wörtwein G, et al. Muscarinic acetylcholine receptor subtypes as potential drug targets for the treatment of schizophrenia, drug abuse, and Parkinson’s disease. ACS Chem Neurosci  2012; 3(2): 80-9.
[http://dx.doi.org/10.1021/cn200110q] [PMID: 22389751] 
[114] 
Gould RW, Dencker D, Grannan M, et al. Role for the M1 muscarinic acetylcholine receptor in top-down cognitive processing using a touchscreen visual discrimination task in mice. ACS Chem Neurosci  2015; 6(10): 1683-95.
[http://dx.doi.org/10.1021/acschemneuro.5b00123] [PMID: 26176846] 
[115] 
Anagnostaras SG, Murphy GG, Hamilton SE, et al. Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat Neurosci  2003; 6(1): 51-8.
[http://dx.doi.org/10.1038/nn992] [PMID: 12483218] 
[116] 
Bell KFS, Zheng L, Fahrenholz F, Cuello AC. ADAM-10 over-expression increases cortical synaptogenesis. Neurobiol Aging  2008; 29(4): 554-65.
[http://dx.doi.org/10.1016/j.neurobiolaging.2006.11.004] [PMID: 17187903] 
[117] 
Haring R, Gurwitz D, Barg J, et al. Amyloid precursor protein secretion via muscarinic receptors: reduced desensitization using the M1-selective agonist AF102B. Biochem Biophys Res Commun  1994; 203(1): 652-8.
[http://dx.doi.org/10.1006/bbrc.1994.2232] [PMID: 8074717] 
[118] 
Caccamo A, Oddo S, Billings LM, et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron  2006; 49(5): 671-82.
[http://dx.doi.org/10.1016/j.neuron.2006.01.020] [PMID: 16504943] 
[119] 
Lebois EP, Schroeder JP, Esparza TJ, et al. Disease-modifying effects of M1 muscarinic acetylcholine receptor activation in an Alzheimer’s disease mouse model. ACS Chem Neurosci  2017; 8(6): 1177-87.
[http://dx.doi.org/10.1021/acschemneuro.6b00278] [PMID: 28230352] 
[120] 
Davis AA, Fritz JJ, Wess J, Lah JJ, Levey AI. Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo. J Neurosci  2010; 30(12): 4190-6.
[http://dx.doi.org/10.1523/JNEUROSCI.6393-09.2010] [PMID: 20335454] 
[121] 
Sheardown MJ. Muscarinic M1 receptor agonists and M2 receptor antagonists as therapeutic targets in Alzheimer’s disease. Expert Opin Ther Pat  2002; 12(6): 863-70.
[122] 
Gautam D, Han S-J, Duttaroy A, et al. Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis. Diabetes Obes Metab  2007; 9(s2)(Suppl. 2): 158-69.
[http://dx.doi.org/10.1111/j.1463-1326.2007.00781.x] [PMID: 17919190] 
[123] 
Gautam D, Jeon J, Li JH, et al. Metabolic roles of the M3 muscarinic acetylcholine receptor studied with M3 receptor mutant mice: a review. J Recept Signal Transduct Res  2008; 28(1-2): 93-108.
[http://dx.doi.org/10.1080/10799890801942002] [PMID: 18437633] 
[124] 
Gautam D, Jeon J, Starost MF, et al. Neuronal M3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth. Proc Natl Acad Sci USA  2009; 106(15): 6398-403.
[http://dx.doi.org/10.1073/pnas.0900977106] [PMID: 19332789] 
[125] 
Wang H, Lu Y, Wang Z. Function of cardiac M3 receptors. Auton Autacoid Pharmacol  2007; 27(1): 1-11.
[http://dx.doi.org/10.1111/j.1474-8673.2006.00381.x] [PMID: 17199870] 
[126] 
Gericke A, Sniatecki JJ, Mayer VGA, et al. Role of M1, M3, and M5 muscarinic acetylcholine receptors in cholinergic dilation of small arteries studied with gene-targeted mice. Am J Physiol Heart Circ Physiol  2011; 300(5): H1602-8.
[http://dx.doi.org/10.1152/ajpheart.00982.2010] [PMID: 21335473] 
[127] 
Bodick NC, Offen WW, Levey AI, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol  1997; 54(4): 465-73.
[http://dx.doi.org/10.1001/archneur.1997.00550160091022] [PMID: 9109749] 
[128] 
Bodick NC, Offen WW, Shannon HE, et al. The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease. Alzheimer Dis Assoc Disord  1997; 11(Suppl. 4): S16-22.
[PMID: 9339268] 
[129] 
Veroff AE, Bodick NC, Offen WW, Sramek JJ, Cutler NR. Efficacy of xanomeline in Alzheimer disease: cognitive improvement measured using the Computerized Neuropsychological Test Battery (CNTB). Alzheimer Dis Assoc Disord  1998; 12(4): 304-12.
[http://dx.doi.org/10.1097/00002093-199812000-00010] [PMID: 9876958] 
[130] 
Jones CK, Eberle EL, Shaw DB, McKinzie DL, Shannon HE. Pharmacologic interactions between the muscarinic cholinergic and dopaminergic systems in the modulation of prepulse inhibition in rats. J Pharmacol Exp Ther  2005; 312(3): 1055-63.
[http://dx.doi.org/10.1124/jpet.104.075887] [PMID: 15574685] 
[131] 
Dencker D, Wörtwein G, Weikop P, et al. Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline. J Neurosci  2011; 31(16): 5905-8.
[http://dx.doi.org/10.1523/JNEUROSCI.0370-11.2011] [PMID: 21508215] 
[132] 
Koshimizu H, Leiter LM, Miyakawa T. M4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition. Mol Brain  2012; 5: 10.
[http://dx.doi.org/10.1186/1756-6606-5-10] [PMID: 22463818] 
[133] 
Pancani T, Foster DJ, Moehle MS, et al. Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice. Proc Natl Acad Sci USA  2015; 112(45): 14078-83.
[http://dx.doi.org/10.1073/pnas.1512812112] [PMID: 26508634] 
[134] 
Ince E, Ciliax BJ, Levey AI. Differential expression of D1 and D2 dopamine and m4 muscarinic acetylcholine receptor proteins in identified striatonigral neurons. Synapse  1997; 27(4): 357-66.
[PMID: 9372558] 
[135] 
Santiago MP, Potter LT. Biotinylated m4-toxin demonstrates more M4 muscarinic receptor protein on direct than indirect striatal projection neurons. Brain Res  2001; 894(1): 12-20.
[http://dx.doi.org/10.1016/S0006-8993(00)03170-X] [PMID: 11245810] 
[136] 
Moehle MS, Pancani T, Byun N, et al. Cholinergic projections to the substantia nigra pars reticulata inhibit dopamine modulation of basal ganglia through the M4 muscarinic receptor. Neuron  2017; 96(6): 1358-1372.e4.
[http://dx.doi.org/10.1016/j.neuron.2017.12.008] [PMID: 29268098] 
[137] 
Foster DJ, Wilson JM, Remke DH, et al. Antipsychotic-like effects of M4 positive allosteric modulators are mediated by CB2 receptor-dependent inhibition of dopamine release. Neuron  2016; 91(6): 1244-52.
[http://dx.doi.org/10.1016/j.neuron.2016.08.017] [PMID: 27618677] 
[138] 
Basile AS, Fedorova I, Zapata A, et al. Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia. Proc Natl Acad Sci USA  2002; 99(17): 11452-7.
[http://dx.doi.org/10.1073/pnas.162371899] [PMID: 12154229] 
[139] 
Steidl S, Yeomans JS. M5 muscarinic receptor knockout mice show reduced morphine-induced locomotion but increased locomotion after cholinergic antagonism in the ventral tegmental area. J Pharmacol Exp Ther  2009; 328(1): 263-75.
[http://dx.doi.org/10.1124/jpet.108.144824] [PMID: 18849356] 
[140] 
Raffa RB. The M5 muscarinic receptor as possible target for treatment of drug abuse. J Clin Pharm Ther  2009; 34(6): 623-9.
[http://dx.doi.org/10.1111/j.1365-2710.2009.01059.x] [PMID: 20175795] 
[141] 
Fink-Jensen A, Fedorova I, Wörtwein G, et al. Role for M5 muscarinic acetylcholine receptors in cocaine addiction. J Neurosci Res  2003; 74(1): 91-6.
[http://dx.doi.org/10.1002/jnr.10728] [PMID: 13130510] 
[142] 
Steidl S, Miller AD, Blaha CD, Yeomans JS. M5 muscarinic receptors mediate striatal dopamine activation by ventral tegmental morphine and pedunculopontine stimulation in mice. PLoS One  2011; 6(11)e27538
[http://dx.doi.org/10.1371/journal.pone.0027538] [PMID: 22102904] 
[143] 
Zhang Y, Huang N-Q, Yan F, et al. Diabetes mellitus and Alzheimer’s disease: GSK-3β as a potential link. Behav Brain Res  2018; 339: 57-65.
[http://dx.doi.org/10.1016/j.bbr.2017.11.015] [PMID: 29158110] 
[144] 
Lucas JJ, Hernández F, Gómez-Ramos P, Morán MA, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J  2001; 20(1-2): 27-39.
[http://dx.doi.org/10.1093/emboj/20.1.27] [PMID: 11226152] 
[145] 
Hernández F, Borrell J, Guaza C, Avila J, Lucas JJ. Spatial learning deficit in transgenic mice that conditionally over-express GSK-3β in the brain but do not form tau filaments. J Neurochem  2002; 83(6): 1529-33.
[http://dx.doi.org/10.1046/j.1471-4159.2002.01269.x] [PMID: 12472906] 
[146] 
Hernández F, de Barreda EG, Fuster-Matanzo A, Goñi-Oliver P, Lucas JJ, Avila J. The role of GSK3 in Alzheimer disease. Brain Res Bull  2009; 80(4-5): 248-50.
[http://dx.doi.org/10.1016/j.brainresbull.2009.05.017] [PMID: 19477245] 
[147] 
Engel T, Lucas JJ, Gómez-Ramos P, Moran MA, Ávila J, Hernández F. Cooexpression of FTDP-17 tau and GSK-3β in transgenic mice induce tau polymerization and neurodegeneration. Neurobiol Aging  2006; 27(9): 1258-68.
[http://dx.doi.org/10.1016/j.neurobiolaging.2005.06.010] [PMID: 16054268] 
[148] 
Kaytor MD, Orr HT. The GSK3 β signaling cascade and neurodegenerative disease. Curr Opin Neurobiol  2002; 12(3): 275-8.
[http://dx.doi.org/10.1016/S0959-4388(02)00320-3] [PMID: 12049933] 
[149] 
Henriksen EJ, Dokken BB. Role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes. Curr Drug Targets  2006; 7(11): 1435-41.
[http://dx.doi.org/10.2174/1389450110607011435] [PMID: 17100583] 
[150] 
Liu Y, Tanabe K, Baronnier D, et al. Conditional ablation of Gsk-3β in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice. Diabetologia  2010; 53(12): 2600-10.
[http://dx.doi.org/10.1007/s00125-010-1882-x] [PMID: 20821187] 
[151] 
Zhu L-Q, Liu D, Hu J, et al. GSK-3 beta inhibits presynaptic vesicle exocytosis by phosphorylating P/Q-type calcium channel and interrupting SNARE complex formation. J Neurosci  2010; 30(10): 3624-33.
[http://dx.doi.org/10.1523/JNEUROSCI.5223-09.2010] [PMID: 20219996] 
[152] 
Suo WZ, Li L. Dysfunction of G protein-coupled receptor kinases in Alzheimer’s disease. ScientificWorldJournal  2010; 10: 1667-78.
[http://dx.doi.org/10.1100/tsw.2010.154] [PMID: 20730384] 
[153] 
Kellett KAB, Hooper NM. The role of tissue non-specific alkaline phosphatase (TNAP) in neurodegenerative diseases: Alzheimer’s disease in the focus In: Sub-cellular biochemistry In:  2015; pp. 363-74.
[154] 
Négyessy L, Xiao J, Kántor O, et al. Layer-specific activity of tissue non-specific alkaline phosphatase in the human neocortex. Neuroscience  2011; 172: 406-18.
[http://dx.doi.org/10.1016/j.neuroscience.2010.10.049] [PMID: 20977932] 
[155] 
Street SE, Kramer NJ, Walsh PL, et al. Tissue-nonspecific alkaline phosphatase acts redundantly with PAP and NT5E to generate adenosine in the dorsal spinal cord. J Neurosci  2013; 33(27): 11314-22.
[http://dx.doi.org/10.1523/JNEUROSCI.0133-13.2013] [PMID: 23825434] 
[156] 
Kellett KA, Williams J, Vardy ER, Smith AD, Hooper NM. Plasma alkaline phosphatase is elevated in Alzheimer’s disease and inversely correlates with cognitive function. Int J Mol Epidemiol Genet  2011; 2(2): 114-21.
[PMID: 21686125] 
[157] 
Vardy ERLC, Kellett KAB, Cocklin SL, Hooper NM. Alkaline phosphatase is increased in both brain and plasma in Alzheimer’s disease. Neurodegener Dis  2012; 9(1): 31-7.
[http://dx.doi.org/10.1159/000329722] [PMID: 22024719] 
[158] 
Martinez-Aguila A, Fonseca B, Hernandez F, Díaz-Hernandez M, Avila J, Pintor J. Tau triggers tear secretion by interacting with muscarinic acetylcholine receptors in New Zealand white rabbits. J Alzheimers Dis  2014; 40(Suppl. 1): S71-7.
[http://dx.doi.org/10.3233/JAD-132255] [PMID: 24503615] 
[159] 
Kristofikova Z, Ripova D, Hegnerová K, Sirova J, Homola J. Protein τ-mediated effects on rat hippocampal choline transporters CHT1 and τ-amyloid β interactions. Neurochem Res  2013; 38(9): 1949-59.
[http://dx.doi.org/10.1007/s11064-013-1101-5] [PMID: 23824558] 
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DOI https://dx.doi.org/10.2174/1567205017666200424134311	Print ISSN 1567-2050
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当代阿耳茨海默病研究

危险联络：Tau与毒蕈碱受体的相互作用

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当代阿耳茨海默病研究

危险联络：Tau与毒蕈碱受体的相互作用

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