阿尔茨海默症发病原因与发病机制的探讨

孙作东*

（黑龙江省亚欧脑科学研究院）

2.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.02.0Ya'ou Brain Science Institute of Heilongjiang province, Harbin 150090 黑龙江省亚欧脑科学研究院15009013704810522045182353728黑龙江省哈尔滨市香坊区赣水路30号sunzuodong@pai314.com孙作东（1966），男，研究员、博士后合作导师，主要研究方向：脑科学基础理论研究与重大脑病康复治疗设备的研发孙作东SUN Zuodong孙作东 2.02.02.02.02.02.02.02.02.02.02.02.02.02.02.01*|*期刊*|*Sun Z D. The Theory of Brain Cell Activation[J]. Journal of US-China Medical Science, 2017, 14(5), 203-211.<CR>2*|*期刊*|*Neyton J, Miller C. Discrete Ba2+ block as a probe of ion occupancy and pore structure in the high-conductance Ca2+ -activated K+ channel[J]. J Gen Physiol, 1988, 92(5): 569-586.<CR>3*|*期刊*|*Armstrong C M, Binstock L. Anomalous Rectification in the Squid Giant Axon Injected[J]. Journal of General Physiology, 1965, 48(5): 859-872.<CR>4*|*期刊*|*Armstrong C M, Hille B. The Inner Quaternary Ammonium Ion Receptor in Potassium Channels of the Node of Ranvier[J]. Journal of General Physiology, 1972, 59(4): 388.<CR>5*|*期刊*|*Mackinnon R, Yellen G. Mutations affecting TEA blockade and ion permeation in voltage- activated K+ channels[J]. Science, 1990, 250(4978): 276-279.<CR>6*|*期刊*|*Yellen G, Jurman M, Abramson T, et al. Mutations affecting internal TEA blockade identify the probable pore-forming region of a K+ channel[J]. Science, 1991, 251(4996): 939-942.<CR>7*|*期刊*|*Heginbotham L, Abramson T, MacKinnon R. A functional connection between the pores of distantly related ion channels as revealed by mutant K+ channels[J]. Science, 1992, 258 (5085): 1152-1155.<CR>8*|*期刊*|*Liu Y, Holmgren M, Jurman M E, et al. Gated Access to the Pore of a Voltage-Dependent K+ Channel[J]. Neuron, 1997, 19(1): 175-184.<CR>9*|*论文集*|*Dong J, Jia J P. Exploring the etiology hypothesis of sporadic Alzheimer's disease from a genetic perspective[A]. Compilation of the 4th National Symposium on Dementia and Cognitive Impairment and Advanced Lectures[C], 2015.<CR>10*|*期刊*|*Kerr M L, Small D H. Cytoplasmic domain of the β-amyloid protein precursor of Alzheimer\chr(34)s disease: Function, regulation of proteolysis, and implications for drug development[J]. Journal of Neuroscience Research, 2005, 80(2): 151-159.<CR>11*|*期刊*|*Nistor M, Don M, Parekh M, et al. Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain[J]. Neurobiology of Aging, 2007, 28 (10): 1493-1506.<CR>12*|*期刊*|*Lott I T, Head E. Alzheimer disease and Down syndrome: factors in pathogenesis[J]. Neurobiology of Aging, 2005, 26(3): 383-389.<CR>13*|*期刊*|*ALZHEIMER’S ASSOCIATION. 2015 Alzheimer’s disease facts and figures[J]. Alzheimers Dement, 2015, 11(3): 332-348.<CR>14*|*专著*|*Han J S. Neuro Science (The third edition) [M] .Beijing: Peking university medical press, 2009.<CR>15*|*期刊*|*Zhao B L, Wan L. Metabolic imbalance of metal ions and early pathogenesis of Alzheimer's disease[J]. Progress in Biochemisry and Biophysics, 2012, 39(8): 756-763.<CR>16*|*期刊*|*Laferla F M, Tinkle B T, Bieberich C J, et al. The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice[J]. Nature Genetics, 1995, 9 (1): 21.<CR>17*|*期刊*|*Jana A, Pahan K. Fibrillar amyloid-bcta peptides kill human primary ncurons via NADPH oxidase-mediated activation of neutral sphingomy-clinase. Implications for Alzheimer’s disease[J]. J Biol Chem, 2004, 279(49): 51451-51459.<CR>18*|*期刊*|*Yang X H, Jiang Z F. Activation of microglia and Alzheimer's disease[J]. Chemistry of Life, 2007, 27(6): 548-550.<CR>19*|*期刊*|*Zhu Y B, Lu P H, Sheng Z H. A New Exploration of the Pathogenesis of AD: Hypothesis of Axoplasmic Transport Obstacles[J]. Progress in Physiological Sciences, 2008, 39(1): 5-9.<CR>20*|*期刊*|*Luo H B, Shi X Q, Li Y, et al. The expression of endoplasmic reticulum A beta binding protein and the effect of stilbene glycoside in behavioral disorders induced by A beta in rats[J].Journal of Apoplexy and Nervous Diseases, 2013, 30(2):128-131.<CR>21*|*期刊*|*Qi J, Peng J X. Degradation of endoplasmic reticulum-related proteins and its mechanism[J]. Chinese Journal of Cell Biology, 2004, 26(2):103-107.<CR>22*|*期刊*|*Lee M H, Siddoway B, Kaeser G E, et al. Somatic APP gene recombination in Alzheimer’s disease and normal neurons[J]. Nature, 2018, 563: 639–645.<CR>23*|*期刊*|*Anand R, Gill K D, Mahdi A A. Therapeutics of Alzheimer’s disease: Past, present and future[J] . Neuropharmacology, 2014.<CR>24*|*期刊*|*Schmitz C, Rutten B P F, Pielen A, et al.Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease[J]. American Journal of Pathology, 2004, 164(4): 1495-1502.<CR>25*|*期刊*|*Williams D R. chr(34)Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tauchr(34)[J]. Internal Medicine Journal, 2006, 36 (10): 652–60. <CR>26*|*期刊*|*Nie J, Shi J S. The role of presenilin in the pathogenesis of Alzheimer's disease[J]. West china journal of pharmaceutical sciences, 2017,32(1): 99-103.<CR>27*|*期刊*|*Edlund C, SöDerberg M, Kristensson K. Isoprenoids in aging and neurodegeneration[J]. Neurochemistry international, 1994, 25(1): 35-38.<CR>28*|*期刊*|*Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways,pathogenesis and therapy[J]. Nat Rev Neurosci, 2009,10(5): 333-334.<CR>29*|*期刊*|*Bu G, Liu C C, Takahisa K. Vascular hypothesis of Alzheimer’s disease: role of apoE and apoE receptors[J]. Molecular Neurodegeneration, 2013, 8(Suppl 1): O20-O20.<CR>30*|*期刊*|*Finch C E, Morgan T E. Systemic Inflammation, Infection, ApoE Alleles, and Alzheimer Disease: A Position Paper[J]. Current Alzheimer Research, 2007, 4(2): 185-189.<CR>31*|*期刊*|*Ashford J W. Treatment of Alzheimer's Disease: The Legacy of the Cholinergic Hypothesis, Neuroplasticity, and Future Directions[J]. Journal of Alzheimers Disease, 2015, 47(1): 149-156.<CR>32*|*期刊*|*Fitzgerald R S, Shirahata M, Ide T, et al. The cholinergic hypothesis revisited-an unfinished story[J]. Biological Signals, 1995, 4(5): 298-303.<CR>33*|*期刊*|*Meraz-Ríos M A, Danira T R, Diana F B, et al. Inflammatory process in Alzheimer's Disease[J]. Frontiers in Integrative Neuroscience, 2013, 7: 59.<CR>34*|*期刊*|*Frank-Cannon T C, Alto L T, Mcalpine F E, et al. Does neuroinflammation fan the flame in neurodegenerative diseases?[J]. Molecular Neurodegeneration, 2009, 4(1): 47.<CR>35*|*期刊*|*Perry V H, Nicoll J A R, Holmes C. Microglia in neurodegenerative disease[J]. Nature Reviews Neurology, 2010, 6(4): 193-201.<CR>36*|*期刊*|*Rotshenker S. The role of galectin-3/mac-2 in the activation of the innate-immune function of phagocytosis in microglia in injury and disease[J]. Journal of Molecular Neuroscience, 2009, 39: 99-103.<CR>37*|*期刊*|*Kaur G, Han S J, Yang I, et al. Microglia and central nervous system immunity[J]. Neurosurgery Clinics of North America, 2010, 21(1): 43-51.<CR>38*|*期刊*|*Luo Y F, Zhang J, Liu N Q, et al. Copper ions influence the toxicity of β–amyloid (1-42) in a concentration-dependent manner in a Caenorhabditis elegans model of Alzheimer’ s disease[J].Sei China Life Sci, 2011, 54(6): 527-534.<CR>39*|*期刊*|*Hodgkin A L, Huxley A F. A quantitative description of membrane current and its application to conduction and excitation in nerve[J]. Physiol, 1952, 117: 500.<CR>40*|*期刊*|*Hodgkin A L, Huxley A F, Katz B. Measurement of current-voltage relations in the membrane of the giant axon of Loligo[J]. The Journal of Physiology, 1952, 116(4): 424-448.<CR>41*|*期刊*|*Hodgkin A L, Huxley A F. A quantitative description of membrane current and its application to conduction and excitation in verve[J]. The Journal of Physiology, 1952, 117 (4): 500-544. <CR>42*|*专著*|*Bear M F. Neuroscience: Explore the brain (Second Edition) [M]. Beijing: Higher Education Press, 2004.<CR>43*|*期刊*|*Doyle D A, Morais Cabral J, Pfuetzner R A, et al. The Structure of the Potassium Channel: Molecular Basis of K+ Conduction and Selectivity[J]. Science, 1998, 280(5360): 69 -77.<CR>44*|*专著*|*Nicholls J G, Robert Martin A, Fuchs P A, et al. From Neuron To Brain (Fifth edition) [M]. England: Sinauer Associates Is an Imprint of Oxford Un, 2011.<CR>45*|*专著*|*Alberts B, Bray D, Hopkin K, et al. Essential Cell Biology(Third Edition)[M]. Boca Raton: CRC Press Inc, 2009.<CR>46*|*期刊*|*Nuttall JR, Oteiza PI. Zine and the aging brain[J]. Genes Nutrit, 2014, 9(1): 1-11.<CR>47*|*期刊*|*Luo Y F, Zhang J, Liu N Q, et al. Copper ions influence the toxicity of β-amyloid(1- 42) in a concentration-dependent manner in a Caenorhabditis elegans model of Alzheimer’s disease[J]. Sci China Life Sci, 2011, 54(6): 527-534.<CR>48*|*期刊*|*Faller P, Hureau C. Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-beta peptide[J]. Dalton Trans, 2009, (7): 1080-1094.<CR>49*|*期刊*|*Hung Y H, Bush A I, Cherny R A. Copper in the brain and Alzheimer’s disease[J]. J Biol Inorg Chem, 2010, 15: 61-76.<CR>50*|*期刊*|*Himes R A, Park G Y, Siluvai G S, et al. Structural studies of copper (I) complexes of amyloid-beta peptide fragments: formation of two-coordinate bis(histidine) complexes[J]. Angew Chem Int Ed Eng1, 2008, 47: 9084-9087.<CR>51*|*期刊*|*Danscher G, Jensen K B, Frederickson C J, et al. Increased amount of zinc in the hippocampus and amygdala of Alzheimer’s diseased brains: a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material[J]. J Neurosci Methods, 1997, 76(1): 53-59.<CR>52*|*期刊*|*Cornett C R, Markesbery W R, Ehmann W D. Imbalances of trace elements related to oxidative damage in Alzheimer’s disease brain [J]. Neurotoxicology, 1998, 19(3):339-345.<CR>53*|*期刊*|*Deibel M A, Ehmann W D, Markesbery W R. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: possible relation to oxidative stress [J]. J Neurol Sci, 1996, 143(1-2): 137-142.<CR>54*|*期刊*|*Ehmann W D, Markesbery W R, Alauddin M, et al. Brain trace elements in Alzheimer’s disease[J]. Neurotoxicology, 1986, 7(1): 195-206.<CR>55*|*期刊*|*Samudralwar D L, Diprete C C, Ni B F, et al. Elemental imbalances in the olfactory pathway in Alzheimer’s disease[J]. J Neurol Sci, 1995, 130(2): 139-145.<CR>56*|*期刊*|*Wenstrup D, Ehmann W D, Markesbery W R. Trace element imbalances in isolated subcellular fractions of Alzheimer’s disease brains[J]. Brain Res, 1990, 533(1): 125-131.<CR>57*|*期刊*|*Lovell M A, Robertson J D, Teesdale W J, et al. Copper, iron and zinc in Alzheimer’s disease senile plaques[J]. J Neurol Sci, 1998, 158(1):47-52.<CR>58*|*期刊*|*Dong J, Atwood C S, Anderson V E, et al. Metal binding and oxidation of amyloid-β within isolated senile plaque cores: Raman microscopic evidence[J]. Biochemistry, 2003, 42 (10): 2768-2773.<CR>59*|*期刊*|*Religa D, Strozyk D, Cherny R A, et al. Elevated cortical zinc in Alzheimer disease [J]. Neurology, 2006, 67(1): 69-75.<CR>60*|*期刊*|*Zhang L H, Wang X, Zheng Z H, et al. Altered expression and distribution of zinc transporters in APP/PS1 transgenic mouse brain[J]. Neurobiol Aging, 2010, 31(1): 74-87.<CR>61*|*期刊*|*Zheng W, Wang T, Yu D, et al. Elevation of zinc transporter ZnT3 protein in the cerebellar cortex of the AβPP/PS1 transgenic mouse[J]. J Alzheimers Dis, 2010, 20(1): 323 -331.<CR>62*|*期刊*|*Friedlich A L, Lee J Y, van Groen T, et al. Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer’s disease[J]. J Neurosci, 2004, 24(13): 3453-3459.<CR>63*|*期刊*|*Cuajungco M P, Faget K Y. Zinc takes the center stage: its paradoxical role in Alzheimer’s disease[J]. Brain Res Brain Res Rev, 2003, 41(1): 44-56.<CR>64*|*期刊*|*Bjorkdahl C, Sjogren M J, Winblad B, et al. Zinc induces neurofilament phosphorylation independent of p70 S6 kinase in N2a cells[J]. Neuroreport, 2005, 16(6): 591-595.<CR>65*|*期刊*|*Suh S W, Jensen K B, Jensen M S, et al. Histochemically-reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer’s diseased brains[J]. Brain Res, 2000, 852(2): 274-278.<CR>66*|*期刊*|*Yokoyama M, Koh J, Choi D W. Brief exposure to zinc is toxic to cortical neurons[J]. Neurosic Lett, 1986, 71(3): 351-355.<CR>67*|*期刊*|*Lutsenko S, Bhattacharjee A, Hubbard A L. Copper handling machinery of the brain[J]. Metallomics, 2010, 2: 596-608.<CR>68*|*期刊*|*Wang H Q, Hu H T. Copper and Alzheimer's disease[J]. Foreign Medical Sciences (Section of Medgeography), 2008, 29(2): 57-59.<CR>69*|*期刊*|*Maynard C J, Cappai R, Volitakis I, et al. Overexpression of Alzheimer’s Disease Amyloid-Opposes the Age-dependent Elevations of Brain Copper and Iron[J]. The Journal of Biological Chemistry, 2002, 277: 44670-44676.<CR>70*|*期刊*|*Huang X D, Cuajungco M P, Atwood C S, et al. Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity[J]. The Journal of Biological Chemistry, 1999, 274: 37111-37116.<CR>71*|*期刊*|*Lovel M A, Robertson J D, Teesdale W J, et al. Copper, iron and zinc in Alzheimer’s disease senile plaques[J]. J Neurol Sci, 1998, 158(1): 47-52.<CR>72*|*期刊*|*Wang Z H, Li L. Copper and Alzheimer's disease[J]. Foreign Medical Sciences (Geriatrics), 2005, 26(5):205-208.<CR>73*|*期刊*|*Virk S A, Eslick G D. Aluminum Levels in Brain, Serum, and Cerebrospinal Fluid are Higher in Alzheimer’s Disease Cases than in Controls: A Series of Meta-Analyses[J]. J Alzheimers Dis, 2015, 47(3): 629-638.<CR>74*|*期刊*|*Que E L, Domaille D W, Chang C J. Metals in neurobiology: probing their chemistry and biology with molecular imaging[J]. Chem Rev, 2008, 108(5): 1517-1549.<CR>75*|*期刊*|*Crapper D R, Krishnan S S, Dalton A J. Brain aluminum distribution in Alzheimer’s disease and experimental neurofi brillary degeneration[J]. Science, 1973, 180: 511-513.<CR>76*|*期刊*|*Perl D P, Brody A R. Alzheimer’s disease: X-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons[J]. Science, 1980, 208: 297-299.<CR>77*|*期刊*|*Yumoto S, Kakimi S, Ohsaki A, et al. Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer’s disease[J]. J Inorg Biochem, 2009, 103: 1579-1584.<CR>78*|*期刊*|*González-Domínguez R, García-Barrera T, Gómez-Ariza J L. Homeostasis of metals in the progression of Alzheimer’s disease[J]. Biometals, 2014, 27: 539-549.<CR>79*|*期刊*|*Cheng S Z, Wang X M, Liu H, et al. Experimental study on the pathogenesis of aluminum-induced Alzheimer's disease model rats[J]. Journal of Apoplexy and Nervous Diseases, 2012, 29(1): 41-43.<CR>80*|*期刊*|*Zhu W Z, Zhong W D, Wang W, et al. Quantitative MR phase-corrected imaging to investigate increased brain iron deposition of patients with Alzheimer disease[J]. Radiology, 2009, 253(2): 497-504.<CR>81*|*期刊*|*Brar S, Henderson D, Schenck J, et al. Iron accumulation in the substantia nigra of patiaents with Alzheimer disease and parkinsonism[J]. Arch Neurol, 2009, 66: 371-374.<CR>82*|*期刊*|*Xiao F, Li X G, Zhang X Y, et al. Combined administration of D-galactose and aluminum induces Alzheimer like lesions in brain[J]. Neurosci Bull, 2011, 27: 143-155.<CR>83*|*期刊*|*Kawahara M, Kato M, Kuroda Y. Effects of aluminum on the neurotoxicity of primary cultured neurons and on the aggregation of β-amyloid protein[J]. Brain Research Bulletin, 2001, 55(2):211-217.<CR>84*|*期刊*|*Walton J R, Wang M X. APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer’s disease[J]. J Inorg Biochem, 2009, 103(11): 1548-1554. <CR>85*|*期刊*|*Justin Thenmozhi A, William Raja T R, Manivasagam T, et al. Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer’s disease[J]. Nutr Neurosci, 2017, 20(6): 360-368.<CR>86*|*期刊*|*Rodella L F, Ricci F, Borsani E, et al. Aluminium exposure induces Alzheimer’s disease-like histopathological alterations in mouse brain[J]. Histol Histopathol, 2008, 23 (4): 433.<CR>87*|*期刊*|*Xie Q, Xu H X, Liu Z, et al. T2map imaging study of rat Alzheimer's disease model[J]. Chinese Journal of Medical Imaging Technology, 2010, 26(s1): 114.<CR>88*|*期刊*|*Hutchinson R W, Cox A G, McLeod C W, et al. Imaging and spatial distribution of beta- amyloid peptide and metal ions in Alzheimer’s plaques by laser ablation-inductively coupled plasma-mass spectrometry[J]. Anal Biochem, 2005, 346(2): 225-233.<CR>89*|*期刊*|*Sparks D L, Schreurs B G, Trace amounts of copper in water induce β-amyloid plaques and learning deficits in a rabbit model of Alzheimer’s disease[J]. J Proc Natl Acad Sci, 2003, 100: 11065-11069.<CR>90*|*论文集*|*Wang Z Y. Brain iron metabolism disorder involved in the pathogenesis and treatment strategy of Alzheimer's disease[A]. Compilation of the 24th National Congress of the Chinese Physiological Society and the Conference of Physiology[C], 2014.<CR>91*|*期刊*|*Wang C Y, Wang T, Zheng W, et al. Zinc overload enhances APP cleavage and Abeta deposition in the Alzheimer mouse brain[J]. PLoS One, 2010, 5: e15349.<CR>92*|*期刊*|*Lu T, Nguyen B, Zhang X, et al. Architecture of a K+ Channel Inner Pore Revealed by Stoichiometric Covalent Modification[J]. Neuron, 1999, 22(3): 571-580.<CR>93*|*期刊*|*Yang J, Elllnor P T, Sather W A, et al. Molecular determinants of Ca2+ selectivity and ion permeation in L-type Ca2+ channels[J]. Nature (London), 1993, 366(6451):158-161.<CR>94*|*期刊*|*Consiglio J F, Andalib P, Korn S J. Influence of Pore Residues on Permeation Properties in the Kv2.1 Potassium Channel. Evidence for a Selective Functional Interaction of K+ with the Outer Vestibule[J]. Journal of General Physiology, 2003, 121(2): 111-124.<CR>95*|*期刊*|*Heinemann S H, Terlau H, Stühmer W, et al. Calcium channel characteristics conferred on the sodium channel by single mutations[J]. Nature (London), 1992, 356(6368): 441-443.<CR>96*|*期刊*|*Palmer A M. The role of the blood–CNS barrier in CNS disorders and their treatment [J]. Neurobiology of Disease, 2010, 37(1): 3-12.<CR>97*|*期刊*|*Brightman M W, Reese T S. Junctions between intimately apposed cell membranes in the vertebrate brain[J]. J Cell Biol. 1969, 40(3): 648-677.<CR>98*|*期刊*|*Wolburg H, Noell S, Mack A, et al. Brain endothelial cells and the glio-vascular complex[J]. Cell and Tissue Research, 2009, 335(1): 75-96.<CR>99*|*期刊*|*Mullins L J. Ion selectivity of carriers and channels[J]. Biophysical Journal, 1975, 15(9): 921-931.<CR>100*|*期刊*|*Nimigean C M, Chappie J S, Miller C. Electrostatic Tuning of Ion Conductance in Potassium Channels[J]. Biochemistry, 2003, 42(31): 9263-9268.<CR>101*|*期刊*|*Hille B. Potassium Channels in Myelinated Nerve: Selective permeability to small cations[J]. Journal of General Physiology, 1973, 61(6): 669.<CR>102*|*期刊*|*Bezanilla F, Armstrong C M. Negative Conductance Caused by Entry of Sodium and Cesium Ions into the Potassium Channels of Squid Axons[J]. Journal of General Physiology, 1972, 60(5): 588-608.<CR>103*|*期刊*|*Huxley A F. Hodgkin and the action potential[J]. J Physiol, 2002, 538:2.<CR>104*|*期刊*|*Roux B T. Ion conduction and selectivity in K(+) channels[J]. Annual Review of Biophysics & Biomolecular Structure, 2005, 34(34): 153-171.<CR>105*|*专著*|*Han Y R. Molecular Cell Biology (The Fourth edition) [M] . Beijing: Science Press, 2012.<CR>106*|*期刊*|*Kuffler S W, Nicholls J G. The physiology of neuroglial cells[J]. Ergeb Physiol, 1966, 57(1): 1-90.<CR>107*|*期刊*|*Kofuji P, Newman E A. Potassium buffering in the central nervous system[J]. Neuroscience, 2004, 129(4): 1043-1054.<CR>108*|*期刊*|*Kofuji P, Ceelen P, Zahs K R, et al. Genetic Inactivation of an Inwardly Rectifying Potassium Channel (Kir4.1 Subunit) in Mice: Phenotypic Impact in Retina[J]. The Journal of Neuroscience, 2000, 20(15): 5733-5740.<CR>109*|*期刊*|*Madsen E, Gitlin J D. Copper and iron disorders of the brain[J]. Annu Rev Neurosci, 2007, 30: 317-337.<CR>110*|*期刊*|*Wang C, Liu P, Wang X L, et al. Metal Ions and Alzheimer's Disease[J]. Sichuan Medical Journal, 2008, 29(4): 467-469.<CR>111*|*专著*|*Phillips R, Kondev J, Theriot J. Physical Biology of the Cell[M]. Beijing: Science Press, 2012.<CR>112*|*期刊*|*Doty R L, Olfaction in Parkinson’s disease and related disorders[J]. Neurobiol Dis, 2012, 46(3): 527-552.<CR>113*|*期刊*|*Ulla M, Bonny J M, Ouchchane L, et al. Is R2* a new MRI biomarker for the progression of Parkinson’s disease? A longitudinal follow-up[J]. PLoS One, 2013, 8(3): e57904.<CR>114*|*期刊*|*Xu J, Gong D D, Man C F, et al. Parkinson’s disease and risk of mortalitv: meta- analvsis and svstematic review[J]. Acta Neurol Scand, 2014, 129(2): 71-79.<CR>115*|*期刊*|*Luckey T D, Venugopal B. Metal Toxicity in Mammals[J]. Chemical Toxicity of Metals and Metalloids, 1978, 2: 32-36.<CR>116*|*期刊*|*Nichols C G, Lopatin A N. Inward rectifier potassium channels[J]. Annual Review of Physiology, 1997, 59(1): 171-191.<CR>117*|*期刊*|*Lu Z. Mechanism of rectification in inward-rectifier K+ channels[J]. Annu Rev Physiol. 2004, 66(1): 103-129.<CR>118*|*期刊*|*Armstrong C M. Interaction of Tetraethylammonium Ion Derivatives with the Potassium Channels of Giant Axons[J]. Journal of General Physiology, 1971, 58(4): 413-437.<CR>119*|*期刊*|*Armstrong C M. Time Course of TEA+-Induced Anomalous Rectification in Squid Giant Axons[J]. Journal of General Physiology, 1966, 50(2): 491-503.<CR>120*|*期刊*|*Lu T, Ting A Y, Mainland J, et al. Probing ion permeation and gating in a K+ channel with backbone mutations in the selectivity filter[J]. Nature Neuroscience, 2001, 4(3): 239 -246.<CR>121*|*期刊*|*Bao H, Hakeem A, Henteleff M, et al. Voltage-insensitive Gating after Charge- neutralizing Mutations in the S4 Segment of Shaker Channels[J]. The Journal of General Physiology, 1999, 113(1): 139-151.<CR>122*|*期刊*|*Bruening-Wright A, Schumacher M A, Adelman J P, et al. Localization of the activation gate for small conductance Ca2+-activated K+ channels[J]. The Journal of Neuroscience, 2002, 22(15): 6499-6506.<CR>123*|*期刊*|*Korn S J, Trapani J G. Potassium channels[J]. IEEE Trans Nanobiosci, 2005, 4(1): 21- 33.<CR>124*|*期刊*|*Flynn G E, Johnson J P Jr, Zagotta W N. Cyclic nucleotide-gated channels: shedding light on the opening of a channel pore[J]. Nature Rev Neurosci, 2001, 2: 643-652.<CR>125*|*期刊*|*Liu Y, Joho R H. A side chain in S6 influences both open-state stability and ion permeation in a voltage-gated K+channel[J]. Pfluegers Archiv European Journal of Physiology, 1998, 435(5): 654-661.<CR>126*|*期刊*|*Heginbotham L, Lu Z, Abramson T, et al. Mutations in the K+ channel signature sequence[J]. Biophysical Journal, 1994, 66(4): 1061-1067.<CR>127*|*期刊*|*Schrempf H, Schmidt O, Kümmerlen R, et al. A prokaryotic potassium ion channel with two predicted transmembrane segments from Streptomyces lividans[J]. The EMBO journal, 1995, 14(21): 5170-5178.<CR>128*|*期刊*|*Heginbotham L, Odessey E, Miller C. Tetrameric stoichiometry of a prokaryotic K+ channel[J]. Biochemistry, 1997, 36(33): 10335.<CR>129*|*期刊*|*MacKinnon R. Determination of the subunit stoichiometry of a voltage-activated potassium channel[J]. Nature, 1991, 350(6315): 232.<CR>130*|*期刊*|*Ketchum K A, Joiner W J, Sellers A J, et al. A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem[J]. Nature, 1995, 376(6542): 690-695.<CR>131*|*期刊*|*MacKinnon R. Structural Conservation in Prokaryotic and Eukaryotic Potassium Channels[J]. Science, 1998, 280(5360): 106-109.<CR>132*|*期刊*|*Mackinnon R, Miller C. Mutant potassium channels with altered binding of charybdotoxin, a pore-blocking peptide inhibitor[J]. Science, 1989, 245(4924): 1382-1385.<CR>133*|*期刊*|*Mackinnon R, Heginbotham L, Abramson T. Mapping the receptor site for charybdotoxin, a pore-blocking potassium channel inhibitor[J]. Neuron, 1990, 5(6): 767-771.<CR>134*|*期刊*|*Hidalgo P, Mackinnon R. Revealing the architecture of a K+ channel pore through mutant cycles with a peptide inhibitor[J]. Science, 1995, 268(5208): 307-310.<CR>135*|*期刊*|*Abbracchio M P, Burnstock G, Verkhratsky A, et al. Purinergic signalling in the nervous system: an overview[J]. Trends in Neurosciences, 2009, 32(1): 19-29.<CR>136*|*期刊*|*Jarvis M F, Khakh B S. ATP-gated P2X cation-channesl[J]. Neuropharmacol, 2009, 56:208-215.<CR>137*|*期刊*|*Skou J C. The influence of some cations on an adenosine triphosphatase from pheripheral nerves[J]. Biochim Biophys Acta, 1957, 23: 394-401.<CR>138*|*期刊*|*Caldwell P C, Hodgkin A L, Keynes R D, et al. The effect of injecting <CR>139*|*期刊*|*Hodgkin A L, Keynes R D. Active transport of cations in giant axons from Sepia and Loligo[J]. J Physiol, 1955, 128(1): 28-60.<CR>140*|*期刊*|*Rizzuto R, Pozzan T. Microdomains of Intracellular Ca2+: Molecular Determinants and Functional Consequences[J]. Physiol Rev, 2006, 86(1): 369-408.<CR>141*|*期刊*|*Carafoli E, Brini M. Calcium pumps: structural basis for and mechanism of calcium transmembrane transport[J]. Curr Opin Chem Biol, 2000, 4(2): 152-161.<CR>142*|*期刊*|*MacLennan D H, Abu-Abed M, Kang C. Structure-function relationships in Ca(2+) cycling proteins[J]. J Mol Cell Cardiol, 2002, 34(8): 897-918.<CR>143*|*期刊*|*Baker P F, Blaustein M P, Keynes R D, et al. The ouabain-sensitive fluxes of sodium and potassium in squid giant axons.[J]. J Physiol, 1969, 200(2): 459-496.<CR>144*|*期刊*|*Skou J C. The Na,K-pump[J]. Methods in Enzymology, 1988, 156:1-25.<CR>145*|*期刊*|*Thomas R C. Membrane current and intracellular sodium changes in a snail neuron during extrusion of injected sodium[J]. J Physiol, 1969, 201: 495-514.<CR>146*|*期刊*|*Thomas R C. Intracellular sodium activity and the sodium pump in snail neurons[J]. J Physiol, 1972, 220: 55-71.<CR>147*|*期刊*|*Jorgensen P L, Hakansson K O, Karlish S J. Structure and mechanism of Na, K-ATPase: functional sites and their interactions[J]. Annual Review of Physiology, 2003, 65: 817-849.<CR>148*|*期刊*|*Zhao J, Zhang Y M, Zheng N Z. Research progress on mechanism of comorbidity of epilepsy and Alzheimer disease[J]. China Medical Herald, 2017, 14(21): 53-56.<CR>149*|*期刊*|*Nelson P T, Schmitt F A, Lin Y, et al. Hippoeampal sclerosis in advanced age: clinical and pathological features[J]. Brain, 2011, 134(5): 1506-1518.<CR>150*|*期刊*|*Palop J J, Chin J, Roberson E D, et al. Aberrant excitatory neuronal activity and compensatory remodelingof inhibitory hippocampal circuits in mouse models of Alzheimer disease[J]. Neuron, 2007, 55(5): 697-711.<CR>151*|*期刊*|*Scarmaes N, Honig L S, Choi H. Seizure in Alzheimer disease: whowhen, and how common [J]. Arch Network, 2009, 66(8): 435-440.<CR>152*|*期刊*|*Amatiniek J C, Hauser W A, DelCastillo-Castaneda C, et al. Incidene and predictors of seizures in patients with Alzheimer disease[J]. Epileosia, 2006, 47(5): 867-872.<CR>153*|*期刊*|*Scharfman H E. Alzheimer’s disease and epilepsy: insight from animal models[J].Future Neurol, 2012, 7(2): 177-192.<CR>154*|*期刊*|*Hall A M, Throesch B T, Buckingham S C, et al. Tau-dependent Kv4.2 depiltion and dendeitic hyperexcitability in a mouse model of Alzheimer disease[J]. J Neurosci, 2015, 35 (15): 6221-6230.<CR>155*|*期刊*|*Glenner G G, Wong C W. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein[J]. Biochem Biophys Res Commun, 1984, 120: 885-890.<CR>156*|*期刊*|*Zhao J, O’Connor T, Vassar R. The contribution of activated astrocytes to Aβ production: implications for Alzheimer’s disease pathogenesis[J]. J Neuroinflamm, 2011, 8:150.<CR>157*|*期刊*|*Citron M, Diehl T S, Gordon G, et al. Evidence that the 42- and 40-amino acid forms of amyloid β protein are generated from theβ-amyloid precursor protein by different protease activities[J]. Proc Natl Acad Sci USA, 1996, 93: 13170-13175.<CR>158*|*期刊*|*Zhang Y W, Thompson R, Zhang H, et al. APP processing in Alzheimer’s disease[J]. Mol Brain, 2011, 4:3.<CR>159*|*期刊*|*Thal D R. The role of astrocytes in amyloid β-protein toxicity and clearance[J]. Exp Neurol, 2012, 236:1-5.<CR>160*|*期刊*|*Nicoll J A, Weller R O. A new role for astrocytes: β-amyloid homeostasis and degradation[J]. Trends Mol Med, 2003,9:281-282.<CR>161*|*期刊*|*Fu W, Shi D, Westaway D, et al. Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity[J]. J Biol Chem, 2015, 290:12504-12513.<CR>162*|*期刊*|*Nagele R G, D’Andrea M R, Lee H, et al. Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer’s disease brains[J]. Brain Res, 2003, 971:197-209.<CR>163*|*期刊*|*Wyss-Coray T, Loike J D, Brionne T C, et al. Adult mouse astrocytes degrade amyloid- β in vitro and in situ[J]. Nat Med, 2003, 9: 453-457.<CR>164*|*期刊*|*Batarseh Y S, Duong Q V, Mousa Y M, et al. Amyloid-β and astrocytes interplay in amyloid-β related disorders[J]. Int J Mol Sci, 2016, 17: 338.<CR>165*|*期刊*|*Kurnellas M P, Adams C M, Sobel R A, et al. Amyloid Fibrils Composed of Hexameric Peptides Attenuate Neuroinflammation[J]. Science translational medicine, 2013, 5(179):179ra42.<CR>166*|*期刊*|*Chemy R A, Legg J T, McLean C A, et al. Aqueous Dissolution of Alzheimer’s Disease A βAmyloid Deposits by Biometal Depletion[J]. J Biol Chem, 1999, 274:23223-23228.<CR>167*|*期刊*|*Bush A I . Metal complexing agents as therapies for Alzheimer's disease[J]. Neurobiology of Aging, 2002, 23(6):1031-1038.<CR>168*|*期刊*|*Bush A I, Tanzi R E. The galvanization of β-amyloid in Alzheimer’s disease[J]. Proc Natl Acad Sci U S A, 2002, 99 (11): 7317-7319.<CR>169*|*期刊*|*Lannfelt L, Blennow K, Zetterberg H, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomized, placebo-controlled trial[J]. Lancet Neurol, 2008, 7(9): 779-786.<CR>170*|*期刊*|*Storr T, Merkel M, Song-Zhao G X, et al. Synthesis, characterization, and metal coordinating ability of multifunctional carbohydrate-containing compounds for Alzheimer’s therapy[J]. J Am Chem Soc, 2007, 129(23): 7453-7463.<CR>171*|*期刊*|*Hamblcy T W. Chemistry: Metal-based therapeutics[J]. Science, 2007, 318(5855): 1392- 1393.<CR>172*|*期刊*|*Cherny R A, Atwood C S, Xilinas M E, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibitsβ-amyloid accumulation in Alzheimer’s disease transgenic mice[J]. Neuron, 2001, 30(3): 665-676.<CR>173*|*期刊*|*Tang Q, Zou W, Sun Z D, et al. Clinical study on transcranial magnetoelectric encephalopathy treatment instrument for Alzheimer’s disease[J]. Highlights of Sciencepaper Online, 2017, 10(11): 1-7.<CR>174*|*在线文献*|*Zou W, Tang Q, Sun Z D, et al. Clinical study on Transcranial magnetoelectric encephalopathy treatment instrument treatmenting vascular dementia[EB/OL]. Beijng: ChinaXiv [2017-01-19] .DOI: 10.12074/201701.00088.<CR>175*|*在线文献*|* Tang Q, Zou W, Sun Z D, et al. Clinical study on Transcranial magnetoelectric encephalopathy treatment instrument treatmenting parkinson’s disease[EB/OL]. Beijng: Sciencepaper Online[2017-02-08]. http://www.paper.edu.cn/releasepaper/content/201702-38.<CR>176*|*论文集*|*Xing X L, Tang Q. Clinical research on influences of transcranial magnetoelectric stimulation on Parkinson’s disease[A]. The assembly of conference papers of the 11th national rehabilitation academic conference of Exercise Therapy Branch of Chinese Association of Rehabilitation Medicine[C], 2011.<CR>177*|*期刊*|*Zhang W, Wang X Y, Guo H Q, et al. Therapeutic effect of repetitive transcranial magnetic therapy on KA induced epileptic rats[J]. Chinese Journal of Neuromedicine, 2018, 17(7): 673-677.<CR>178*|*期刊*|* Xia X Y, Yang Y, Bai Y, et al. Application of transcranial magnetic stimulation combined with electroence-phalography in consciousness discrimination of patients with disturbance of consciousness[J]. Chin J Neuromed, 2016, 15(4): 425-428.<CR>179*|*期刊*|*Kimiskidis VK, Valentin A, Kälviäinen R. Transcranial magnetic stimulation for the diagnosis and treatment of epilepsy[J]. Curr Opin Neurol, 2014, 27(2): 236-241.<CR>180*|*期刊*|*Ruffolo G, Di BC, Cifelli P, et al. A novel action of lacosamide on GABAA currents sets the ground for a synergic interaction with levetiracetam in treatment of epilepsy[J]. Neurobiol Dis, 2018, 115: 59-68.<CR>181*|*期刊*|*Jiang Z, Guo M, Shi C, et al. Protection against cognitive impairment and modification of epileptogenesis with curcumin in a post-status epilepticus model of temporal lobe epilepsy [J].Neuroscience, 2015, 310: 362-371.<CR>182*|*期刊*|*Liu A, Bryant A, Jefferson A, et al. Exploring the efficacy of a 5-day course of transcranial direct current stimulation (TDCS) on depression and memory function in patients with well-controlled temporal lobe epilepsy[J]. Epilepsy Behav, 2016, 55: 11-20.<CR>183*|*期刊*|*Tang A, Thickbroom G, Rodger J. Repetitive Transcranial Magnetic Stimulation of the Brain:Mechanisms from Animal and xperimental Models[J]. Neuroscientist, 2015, 23(1): 1-13.<CR>184*|*专著*|*Bear M F, Connors B W, Paradiso M A. Synaptic Transmission. In: Neuroscience: exploring the brain[M]. Philadelphia: Lippincott Williams, wilkins inc, 2001.<CR>185*|*期刊*|*Burgoyne R D, Morgan A. Secretory granule exocytosis[J]. Physiological Reviews, 2003, 83(2): 581-632.<CR>186*|*期刊*|*Schneggenburger R, Neher E. Presynaptic calcium and control of vesicle fusion[J]. Current Opinion in Neurobiology, 2005,15(3): 266-274.<CR>187*|*期刊*|*Rizo J, Chen X, Arac D. Unraveling the mechanisms of synaptotagmin and SNARE function in neurotransmitter release[J]. Trends Cell Biol, 2006, 16(7): 339-350.阿尔茨海默症发病原因与发病机制的探讨|Study on the cause and pathogenesis of Alzheimer's disease|*|1|孙作东|SUN Zuodong|黑龙江省亚欧脑科学研究院|Ya'ou Brain Science Institute of Heilongjiang province, Harbin 150090 |孙作东（1966），男，研究员、博士后合作导师，主要研究方向：脑科学基础理论研究与重大脑病康复治疗设备的研发|黑龙江省哈尔滨市香坊区赣水路30号|150090|sunzuodong@pai314.com|045182353728|13704810522

摘要：目的：一个基于脑细胞激活论的启发性观点，是应用细胞的物理生物学原理在分子水平对散发性阿尔茨海默（AD）发病原因及发病机制的探讨，目的是协调统一已有AD病因学说，解决长期以来困扰神经元退行性变疾病研究领域源头问题。方法：1.论述与已有假说的关系；2.生物物理学、医学病理学、生物学模型的证明；3.解释及AD解决方案。结果：1. Aβ不是AD致病原因，而是脑细胞异常凋亡后的遗骸；2.引起膜电位巨大改变的K+浓度差是有效浓度；3. 钾通道异常受损，钠离子提前进入胞内占钾位；4. AD是物理病，治疗应首选物理手段。结论：过量阳离子从细胞外转入细胞内，在细胞膜内表面与钾离子产生竞争性占位，并因此消减膜电位，使所产生的动作电位无法正常激活钙离子通道，最终导致脑细胞异常凋亡。淀粉样斑点是脑细胞异常凋亡后的遗骸，淀粉样斑块是淀粉样斑点之间通过范德华力、静电吸引力聚集而成，间质为淀粉样蛋白。脑细胞依次包含神经元、小胶质细胞、星形胶质细胞，其遗骸形成斑点的核多为阳离子。AD预防的外因在环境，尤其是重金属离子，内因则是身体酸碱度；AD治疗应首选经颅磁电刺激技术。因本文核心观点——阳离子占钾位是AD始发因素，所以将这一病因学说命名为鸠子论，取汉语成语鸠占鹊巢之意。

关键词：阿尔茨海默；病因学说；阳离子占位；淀粉样斑块；细胞遗骸；物理手段

中图分类号：Q291

Study on the cause and pathogenesis of Alzheimer's disease

SUN Zuodong

(Ya'ou Brain Science Institute of Heilongjiang province, Harbin 150090)

Abstract:Objective: This is a heuristic view based on brain cell activation theory， the cause of disease and pathogenesis of sporadic AD is discussed at molecular level by applying the principles of cell physics and biology. The purpose of this paper is to harmonize the existing theories of etiology of AD and to solve the source problems that have plagued the research field of neurodegenerative diseases for a long time. Method: 1.Discuss the relationship with the existing hypothesis; 2. Demonstration of Biophysics, Medical Pathology and Biological Model; 3. Explanation and AD Solutions. Result: 1. Abeta is not the cause of AD, but the remains of brain cells after abnormal apoptosis; 2. The K + concentration difference of which causes the great change of membrane potential is the effective concentration; 3. Potassium channels are abnormally damaged and sodium ions enter the cell ahead of time to occupy the potassium position; 4. AD is a physical disease. especially transcranial magnetoelectricity stimulation, should be the first choice for treatment. Conclusion: Excess cations are transferred from extracellular to intracellular. They compete position with potassium ions on the inner surface of cell membranes, thus abatementing the membrane potential, making action potential unable to activate calcium channels normally, which eventually leads to abnormal apoptosis of brain cells. Amyloid plaque are the remains of abnormal apoptotic brain cells. Amyloid plaque is the aggregation of amyloid spots by van der Waals force and electrostatic attraction, and its interstitium is amyloid protein.Brain cells consist of neurons, microglia and astrocytes in turn. Most of the spotted nuclei in the remains are cations. The external factor of prevention is environment, especially heavy metal ions, the internal cause is body acidity and alkalinity; Transcranial magnetic stimulation technique should be the first choice for AD treatment. The position of cation occupying potassium is the initiating factor of AD, so the etiology theory is named Theory of dove-like particles. Take the Chinese idiom "Turtledove occupies the nest of magpies".

Keywords: Alzheimer; etiology; cationic placement; amyloid plaque; cell remains; physical means

引言

阿尔茨海默病（AD）是一种最常见的神经元退行性疾病。目前，全球有大约3560万人，人口老龄化使AD的患病率呈急剧增高趋势。AD患者的主要临床表现是进行性记忆障碍，其主要病理学特征则是在脑中形成大量的老年斑和神经元纤维缠结以及出现弥漫性脑萎缩，早在1906年由阿尔茨海默所描述，但其真正的病因及发病机制的研究，在此后的一百多年里，并无显著进展和明确答案，仍在几大猜想和假说间徘徊。

本文就是在这样背景下的一个基于脑细胞激活论[1] 的启发性观点，是应用细胞的物理生物学原理在分子水平对散发性AD发病原因及发病机制的探讨，其目的是协调统一已有AD病因学说，解决长期以来困扰神经元退行性变疾病研究领域的源头问题。

基本内容：过量阳离子从细胞外转入细胞内，在细胞膜内表面与钾离子产生竞争性占位，并因此消减膜电位，使所产生的动作电位无法正常激活钙离子通道[2]，最终导致脑细胞异常凋亡。淀粉样斑点是脑细胞异常凋亡后的遗骸，淀粉样斑块是淀粉样斑点之间通过范德华力、静电吸引力聚集而成，间质为淀粉样蛋白。脑细胞依次包含神经元、小胶质细胞、星形胶质细胞，其遗骸形成斑点的核多为阳离子。

阳离子分无机和有机二类，其中无机阳离子多指向Cu2+、Zn2+、AL3+、Fe2+等过渡金属离子；有机阳离子则指MPP+、四乙基铵离子（TEA）、多聚胺类物质及低于等电点的胞内蛋白质等。MPP+是MPTP进入脑内后在胶质细胞单胺氧化酶B的催化下形成的活性有机物，MPTP为1-甲基-4苯基-1，2，3，6-四羟吡啶，存在于海洛因杂质中；多胺以带正电荷多聚阳离子状态存在，可通过氢键和离子键形式与核酸、蛋白质及磷脂相结合；TEA是一种钾通道不能通透的有机阳离子，但可在胞膜双侧堵塞钾离子通道[3-8]，相当于占钾位。

阿尔茨海默病可分为散发性和家族性两大类，通常认为家族性AD具有明显的家族聚集特征，而散发性AD至今其发病机制还不清楚[9]。本文仅针对散发性AD神经元的异常凋亡，不探讨非正常生理条件下如受到物理、化学因素损伤或遗传因素等引发的神经元坏死。因本文核心观点—阳离子占钾位是AD始发因素，所以将这一病因学说命名为鸠子论，取汉语成语鸠占鹊巢之意。“鸠”代表非必需阳离子，“鹊”系指有效钾离子，“巢”喻有效钾离子位置（见图1、图2）。

与Aβ、tau蛋白等假说的关系

AD病因学说，主要有Aβ蛋白假说、tau蛋白假说、早老素(PS) 假说、载脂蛋白E（ApoE）假说、胆碱能假说、炎症假说、金属离子代谢紊乱假说等，其中比较主流的观点集中在Aβ蛋白堆积以及 Tau 蛋白过度磷酸化两方面。

Aβ蛋白假说

Aβ蛋白假说[10-12] 认为，老年斑的形成与积累是AD的主要病因。老年斑的主要成分是β-淀粉样多肽（Aβ），由一组39～43个氨基酸残基组成，是APP经酶切后产生的一个肽段。Aβ来自于淀粉样蛋白前体（APP），是所有神经系统所有细胞APP代谢的正常产物[13]。在正常情况下，Aβ的产生和降解保持平衡。基于这一假说的药物研究主要集中在降低Aβ的生成、增加Aβ的清除或阻断Aβ的聚合上。至今30多年，还没有任何一种真正有效的药物问世[14]。

图1 阳离子占钾位机制

Zn2+ Cu2+ Fe2+为2价阳离子，各占了2个钾离子位置抵消了2个阴离子，Al3+占了3个钾位抵消了3个阴离子，因此消减膜电位，动作电位无法激活Ca2+通道。胞内细胞器及细胞质间的“+ -”，表示已经处于“稳态”，约占所有K+ 99.99999%，基本不参与膜电位活动;仅0.00001% K+膜内外交流。

图2 占钾位影响动作电位机制

蓝色代表正常膜电位的生成及动作电位的活动，红色为异常神经元的膜电位及动作电位的发放频率。如膜电位降至50%，动作电位幅值无法达到激活Ca2+通道的阈值。膜电位去极化与复极化时程可能会由2ms缩减至1ms，无效动作电位发放频率也会增加一倍，钠-钾泵消耗的ATP能量也将翻倍。

所以，有学者认为Aβ不是AD病理损害的初始和主要损害机制，而仅仅是AD病理损害过程中伴发的病理标志[15]，关于它们在一定程度上可能反过来加重AD的病理损害的观点，也存有争议——如果淀粉样蛋白是有害的，那么在多发性硬化症小鼠模型中敲除或抑制这些蛋白应该对疾病有所缓解,但研究显示上述措施只会加重小鼠的病情。

研究人员据此指出，Aβ实际上是机体为了保护自身而合成的，在机体内非常普遍，这些蛋白作为分子伴侣发挥作用，能够在损伤位点附近帮助清除与炎症和免疫应答有关的有害分子。

另外，Aβ可能发挥毒性作用的机制又衍生了诸多辅助性假说，如Aβ纤维聚合假说[16,17]、受体中介假说[14]、小胶质细胞中介假说[18]、神经细胞轴浆转运障碍假说[19]、内质网相关蛋白-Aβ复合物毒性假说[20,21] 等，使AD问题变得愈加复杂和棘手，这不符合一个科学假说的简捷性原则。

最近，又有研究者发现，在AD患者神经细胞内编码β-淀粉样蛋白前体的 APP 基因发生了大量重排和突变，其中一些突变更是为AD患者所独有[22]，似乎又为Aβ蛋白假说提供了新的证据，想表达的意思是：过去几十年的研究并没有白费，可作为临床药物开发的新思路。

Aβ蛋白假说，使研究者们集体陷入了沉默成本效应的怪圈，似乎到了“too big to fail”的地步。本文的主要观点之一，是将过量Aβ与AD之间的“因果”关系做了一下“颠倒。

tau、PS、ApoE假说

tau蛋白假说[23-25] 认为，tau蛋白异常磷酸化和聚集是AD发病的主要原因。tau蛋白是神经细胞主要的微管蛋白，参与微管组装和稳定突触传递机制。正常tau蛋白是一种含磷蛋白质，每克分子tau蛋白的磷酸含量为2～3克分子，而AD患者每克分子tau蛋白的磷酸含量为5～9克分子，是正常水平的2～3倍。当tau蛋白被过度磷酸化并在细胞内聚集时，可抑制微管组装，破坏微管的稳定性，从而损伤轴突转运系统，结果导致突触丢失及逆行性退行性变性的发生。

tau蛋白异常，在AD的发病中起重要作用，还参与了其他20余种神经退行性疾病的病理过程，有学者认为tau蛋白异常是Aβ上游事件。

PS假说[26,27] 认为，PS可能通过调节γ-分泌酶对APP切割及影响tau蛋白磷酸化而在AD病理过程中起作用。PS包括PS-1（467个氨基酸）和PS-2（488个氨基酸），两者高度同源。PS参与细胞内钙信号途径的调节，如调节β-连环素的稳定性、膜蛋白的运输和钙依赖性凋亡等。约50～80%家族性AD与PS-1和PS-2基因突变有关。

ApoE假说[28-30] 认为，ApoE的作用类似于神经营养因子，大量存在于AD患者老年斑以及由tau过度磷酸化导致的胞内神经缠丝（NFT）中[15]。ApoE是迄今所知的唯一与神经系统关系密切的载脂蛋白，由299个氨基酸残基组成，分子量为34KD。在中枢神经系统，ApoE主要由星形胶脂细胞产生，是最重要的脂质转运体。神经再生之初，损伤局部大量脂质聚集，间质中的巨噬细胞游走于损伤部位，合成和分泌ApoE以捕捉脂质小体并储存于巨噬细胞中，其携带的脂质将用于轴索和髓鞘的再生。

Tau、PS、ApoE只是在β-淀粉样蛋白的上行或下行通路起作用，尽管受到了研究者们的重视，但与Aβ一样同属于AD神经元发生退行性变的后期事件。

胆碱能假说

胆碱能假说[31,32] 认为，基底前脑(basal forebrain)胆碱能神经元丧失和与之有关的酶活性显著下降是AD患者最突出的病理学和神经化学特征，是AD患者发生学习、记忆障碍的主要原因。

这一假说得到了药理学、生物化学和电生理学研究证据的广泛支持，也包括作者本人在脑细胞激活论[1] 中支持了这一假说，但脑细胞激活论中有关“脑内胆碱能神经元发生选择性退行性变是不争的事实”的表述，现在看来是不够严谨的。脑内胆碱能神经元发生退行性变是因为脑内胆碱能神经元集中区所处的特殊位置——基底前脑决定的，而不是发生“选择性退行性变”，借此机会对脑细胞激活论的不当表述予以修正。

胆碱能假说仅能解释AD记忆障碍发生机制，但与本文不矛盾，而且还被本文观点全覆盖。

炎症假说

炎症假说[33,34] 认为，炎症因子是导致AD神经元发生退行性变的主要因素。神经炎症是AD大脑中的一个显著特征，AD患者脑内的炎症反应，即小胶质细胞和星形胶质细胞的活化，又具体表现在其数量增加、体积增大、能动性增强和分泌多种炎症因子上。目前，人们广泛认为这些炎症因子参与的免疫反应与AD的病理进展密切相关[35-37]。小胶质细胞约占胶质细胞总数的5%～20%左右，是脑中的巨噬细胞，也是脑实质中唯一的一种免疫细胞，因而被看作是中枢神经系统抵御病原入侵的第一道防线。

本文观点认为，炎症因子不是导致AD神经元发生退行性变的初始因素，是小胶质细胞应对β-淀粉样斑点、斑块的正常免疫反应，很可能是有益无害的。

金属离子代谢紊乱假说

金属离子假说[38] 认为，脑内金属离子代谢失衡与AD有关，铁、铜等金属离子缺乏可能主要与AD早期关系密切，而铁、铜等金属离子过载可能主要与AD后期损伤关系密切，该学说在AD发生发展中的重要性已引起研究者广泛关注（见图3）。

图3 人体必需微量元素

红色标示的四种元素，占人体原子总数99%；蓝色标示的七种元素，占人体原子总数0.9%；绿色标示的其它一些原素是人体必需的微量元素；黄色标示的元素，目前还不清楚是否是人体所必须。人体必需的微量元素不能过量超标，如胞外钾离子过量会影响膜电位，钠离子会提前混入胞内占钾位。

本文支持了该学说的部分观点，与其区别在于：本文所指阳离子不局限于无机金属阳离子，还包括了有机阳离子；本文对发病机制的阐释重点应用了生物物理学原理，该学说应用的是氧化应激反应等生物化学原理，不能兼容其它学说。

论证

本文虽然不支持或不完全支持以上AD各种病因学说，但可将这些学说的依据转化为理所当然得出的结论，作为支持本文观点的证据。

生物物理学证明

动作电位过程中，细胞的去极化是由钠离子跨膜内流引起的，而复极化是由钾离子的外流所致，这为Hodgkin和Huxley实验所证实：动作电位的上升相由gNa瞬时增大和钠离子内流所引起，其下降相与gK的增加和钾离子外流有关[39-41]。

K+浓度微小变化会引起膜电位巨大改变。应用Nernst方程，对一个直径50μm，含100mmol/L K+的细胞，进行离子浓度与平衡电位值之间关系的计算，得出膜从0mV～-80mV需要的浓度变化约0.00001mml/L。K+外流达到平衡后，胞内K+浓度从100mmol/L降至99.99999mmol/L，是千万分之一（1/10000000）的变化[42]。

Nernst方程：

为离子平衡电位，R为气体常数，T为绝对温度，Z为离子电荷，F为法拉第常数，log为以10为底数的对数，为细胞外离子浓度， 为细胞内离子浓度。在体温条件下，K+的Nernst方程可简化为：

= 61.54 若 = 且=1.3

那么= 61.54

直径50μm 细胞：

胞体积 = 65416.66667μm³

表面积 = 7850μm²

那么，这个千万分之一的浓度差究竟相当于多少个K+呢？我们接着推算：1L=1015μm³，相当于6个/μm³，整个细胞流出的K+为393808≈40万个，相当于膜内表面50个/μm²。按单个神经元有2000个K+通道计算，那么4μm²就共享了一个K+通道。也就是说，一个动作电位的冲程，每个K+通道只有200个K+流出或转入。

理论上，一个钾离子通道在1s内的通透能力为108钾离子[43]，而实际推算的结果是：引起膜电位0mV～-80mV巨大改变的仅需K+浓度千万分之一的变化，相当于400000个/次、50个/μm²、6个/μm³、200个/通道。产生一次动作电位，单个离子通道流出或转入K+确实不是一个大数字。但是，从细胞的结构与功能来衡量，这个数字却隐藏着极大的秘密。

只有这0.00001%的浓度差为有效浓度，富集于胞内膜表面或少量游离于细胞器之间，真正参与了膜电位的活动。其余的99.99999%的钾离子，抵消了胞内阴离子或有机分子上的负电荷而处于“稳态”，存在于细胞核、细胞器里，或少量的稳定在细胞器间，相对于膜电位的产生，可以视为无效浓度。所以，特定离子的活化率之比不可以等同于浓度之比。应用Nernst方程，采用浓度比值计算法，可推导出膜电位的变化与K+浓度变化之间的关系并不密切的结论[44]，但没有反应“千万分之一”的问题。

任何阳离子，如K+流出胞外总会在胞内留下未抵消的负电荷，由此产生了电场或膜电位，这种膜电位将对抗K+进一步向胞外迁移，约在1ms之内达成平衡[45]。换个说法，任何非必需阳离子“混入”胞内而滞留在胞内膜表面，都会抵消膜内表面负电荷。此时，非必需阳离子已经占了钾位，影响了钠-钾泵从胞外向胞内转运K+的数量。如果是二价阳离子，一个将抵消二个负电荷，代替了二个K+。以Zn2+为例，脑内大约85%的Zn2+与金属蛋白结合而处于稳态，15%左右的Zn2+呈游离状态。Zn的密度为7.14g/cm³，大于4.5g/cm³，所以Zn2+极易沉积到胞内膜表面，与膜内表面的钾离子形成竞争性占位，会极大地消减膜电位，当达到某一阈值时所产生的动作电位将无法正常激活电压门控Ca2+通道，最终导致神经元步入凋亡程序并异常死亡。过量阳离子占钾位对膜电位所产生的巨大影响，用“膜去极化”一词来表达是不准确的。

同样，膜电位对胞外钾浓度的变化也很敏感，如胞外K+浓度10倍的变化，即K+浓度由5mmol/L增加到50mmol/L，将使膜电位由-65mV变至-17mV [42]，引起了膜电位70%以上的变化。

以上数值仅是估算，不同版本教材的估算值出入比较大[44,45]，不过都明确地表达了这样的一个观点，即用于建立细胞膜电位而进入带电层的K+对细胞内K+浓度并无显著影响[44]，即千万分之一的浓度变化可以忽略不计[42]。这正是作者极力想纠正并在文中竭力提醒研究者要高度重视的关键问题点：应用Nernst方程的目前算法，不能真正反映有效离子浓度与产生膜电位的事实关系，这个千万分之一的浓度差就是有效浓度，绝对不可以“忽略不计”，这是问题关键之所在。

医学病理学证明

目前，能够确定的是，β淀粉样蛋白是检测AD的一种生物标记[15]。大量研究表明，AD患者大脑神经元外出现大量淀粉样蛋白堆积形成的老年斑与高浓度金属离子共存，包括锌（约1mmol/L）、铜（约0.4mmol/L）、铝（约0.88mmol/L）、铁（约0.9mmol/L）等[46-50]。

对晚期AD患者尸检发现，在海马、杏仁核和多个新皮质区域锌含量显著增高[51-56]。应用原子吸收光谱和微粒诱导X射线发射（micro-PIXE）等手段证实AD患者老年斑内锌含量高达1055mmol/L，而在同龄对照组的神经纤维网内锌含量仅为350mmol/L [57]。Dong等[58] 将AD患者大脑老年斑分离出来后应用Rman显微镜观察并确定其结构和组成，发现锌离子与组氨酸残基的分布一致。Rehga等[59] 对10例AD患者和14例同龄对照组尸检皮层中锌离子的含量进行检测，发现AD患者皮层中锌离子的含量是对照人群的2倍以上，绝大多数晚期AD患者皮层锌离子水平显著增高。应用金属自显影技术发现锌离子大量聚集在Aβ老年斑内[60,61]，尤其是在神经炎性斑块的Aβ核心和失营养状态的神经元突起中富集，淀粉样血管病变部位也可见到大量锌离子沉积[60,62]。在AD病变的易损伤部位，如海马和杏仁核，均可检测到锌离子浓度异常升高[51-56,63]。体外研究发现锌离子能诱导Tau蛋白过度磷酸化[64]。晚期AD患者脑内锌离子的增加与神经原纤维缠结的出现相一致，而且在存在神经原纤维缠结的神经元内锌离子含量明显增高[65]。体外研究表明，用300～600μmol/L的锌离子处理15min即可导致培养的大脑皮层神经元广泛死亡[66]。

铜的推荐摄入量为0.9mg/d。健康人体内含铜110mg，而脑内大约含铜9mg，适量的铜对人体有重要意义。正常细胞游离铜的浓度每个细胞平均不到1个原子水平[67,68]。Maynard 等[69] 研究发现，随着年龄的增长铜离子在脑组织内水平显著升高，在老年斑中Cu2+有异常高的浓度(约0.4 mmol/L) [70]。Lovel等[71] 使用粒子发射（PIX）在老年斑中测量发现AD患者脑中铜离子含量为正常人的1.5倍。Atwood等[72] 报道尸检发现AD患者老年斑内铜、铁和锌的浓度分别为390μmol/L、940μmol/L、1055μmol/L，明显高出对照组70μmol/L、 340μmol/L、350μmol/L，并伴有铜、铁和锌相关蛋白的改变，AD患者脑脊液的浓度较正常水平增高2.2倍。

铝并非人体所必需，但研究结果显示，慢性铝中毒个体发生AD的概率高达71% [73,74]。早在1973年，Crapper等[75] 发现铝在AD患者大脑内某些区域聚集，并能诱导高等动物神经纤维的退化。1980年，Perl和Brody [76] 利用扫描电子显微镜和X-射线荧光光谱的方法，分别检测了AD患者和正常老年人尸体海马神经元中铝的含量，结果表明，无论是AD患者还是正常老年人，铝在神经元纤维缠结比例较高的神经元中均显著增多，而相邻正常神经元中几乎没有铝沉积。Yumoto等[77] 利用能量衍射X射线光谱技术结合透射电子显微镜（TEM-EDX）技术探究铝在AD患者脑中的作用，结果显示，铝参与了Aβ聚集形成神经元毒性纤维的过程，并可能诱导Aβ形成β-折叠结构。Gonzalez-Dominguez等[78] 对AD发病过程中金属动态平衡的研究表明，铝介导的神经毒性主要作用于小分子物质，而且，血液中铝的浓度异常也会影响其它金属元素的分布，扰乱血清中金属的动态平衡。目前已证实，减少铝的摄入是预防AD的有效措施[79]。

虽然铁离子没有与Aβ直接相互作用关系，但AD患者脑内铁的含量与疾病发展呈正相关，随着年龄的增长，铁离子会在苍白球、尾状核以及壳核大量沉积，以苍白球为著，这应是“淀粉样斑点是脑细胞异常凋亡后的遗骸”的观点的直接证据。研究还发现在老年斑中 Fe3+有异常高的浓度(约1 mmol/L) [70]。朱文珍等[80] 发现，AD患者脑内铁含量在双侧海马、顶叶、壳、尾状核、齿状核处明显高于正常对照组。Brar等[81] 研究表明，铁的累积会加据AD的发病过程。

生物学模型证明

金属离子能够导致AD，已被国内外研究者大量基础实验所证实，特别是用金属离子成功地制作了AD动物模型，作为有力证据支持了本文的核心观点。

耿海局、罗焕敏等[82] 在D-半乳糖制作亚急性衰老模型的基础上，联合应用三氯化铝，成功地制备了AD动物模型，模型鼠表现出明显的学习记忆障碍、脑内乙酰胆碱（ACh）水平降低、乙酰胆碱转移酶（ChAT）和胆碱脂酶（CHE）活性下降，并出现了老年斑和神经原纤维缠结等病理改变。Kawahara 等[83] 使用小鼠大脑皮层神经元，原代培养后作为一种体外的模式体系来研究铝对 Aβ聚积及其神经毒性，发现加入 50 mmol/L 氯化铝3周以后，神经元发生形态学改变并且出现 Aβ聚积。他们也使用了免疫印迹法在体外检测了Aβ的多聚化过程，证明了铝诱导了Aβ肽构象的改变并且在体外增强了 Aβ聚积。程书珍等[79] 对铝诱导AD模型大鼠进行研究，证实铝的过多摄入使大鼠胆碱能系统失衡而导致AD发病。发现中高剂量铝饲料组大鼠海马中乙酰胆碱酯酶（AchE） 的活性明显增高，ChAT活性明显降低，ACh含量显著减少。

Walton等[84] 给予大鼠AlCl3 (1.7mg/kg·d)喂养4个月，发现海马和皮层组织APP基因表达升高。Rui等给予ICR小鼠AlCl3(10mg/kg·d)口服100d，发现小鼠海马和皮层MDA水平升高，SOD活性降低，海马和皮层神经元出现DNA氧化损伤。成年雄性Wistar大鼠口服AlCl3(17mg/kg· d)处理6周诱导AD样病理，与对照组相比，模型组大鼠出现神经胶质细胞激活和神经元萎缩。Justin等[85] 对雄性Wistar大鼠腹腔注射AlCl3(100mg/kg·d)60d，大鼠出现显著的学习记忆缺陷，神经元凋亡增加。Rodella等[86] 用2.5%硫酸铝水溶液喂养小鼠12个月，小鼠出现与Aβ类似沉淀的淀粉样血管病，Aβ蛋白在海马和皮质层沉积显著增多。小鼠给予AlCl3（60mg/kg），连续7d，对比AD模型小鼠进行避暗实验，发现该模型小鼠空间记忆学习能力下降。

铜也发现可以加剧AD病理变化。有研究人员用双侧颈动脉结扎联合高Cu2+喂养诱导AD鼠模型，发现在Morris测试中，模型组比仅用双侧颈动脉结扎的对照组的逃避潜伏时间明显延迟，并出现类似老年斑的结构，皮质和海马区出现Aβ样免疫反应阳性细胞[87]。Hutchinson等[88] 也在转基因鼠实验中证实了铜离子水平确有提高。Sparks [89] 在给兔子饲喂高胆固醇饮食的同时，在其饮水中加入微量的铜（0.12ppm），结果与相同条件下饲喂蒸馏水的对照组相比，老年斑的生成明显增多，而且更接近于人类的老年斑，同时伴有兔子认知功能的损伤。

王占友等[90] 用高铁饮用水喂养AD转基因鼠，加剧其脑内Aβ沉积和tau蛋白磷酸化。王春艳等[91] 也发现，APP/PS1转基因小鼠长期使用高锌含量的饮用水会导致大脑APP表达增加、裂解和Aβ沉积。

解释

我们假设以上的观点与论证是正确的，在这个前提下有必要对和本文核心观点密切相关的一些问题逐一进行讨论，即使有些论据不够充分或不够直接也无妨，可作为本文观点的旁证一并提及。

离子通道与血脑屏障

离子通道，需要4～6个相似的蛋白质分子聚合，并在其中央形成一个孔道。离子通道虽有数百种，但大多数都有离子选择性，这是由孔道的直径和孔道内部R基团性质决定的，通道蛋白质可悬浮在脂质双层中，其疏水性部分位于膜内，而亲水性两端露于两侧的水环境中[92-95]。血脑屏障，是指脑毛细血管壁与神经胶质细胞形成的血浆与脑细胞之间的屏障和由脉络丛形成的血浆和脑脊液之间的屏障，这些屏障能够阻止某些物质由血液进入脑组织，血液中多种溶质从脑毛细血管进入脑组织，有难有易；有些很快通过，有些较慢，有些则完全不能通过[96-98]。

通透选择的相对性

它们的通透选择能力是进化所得，对离子的选择性是相对的。

以钾离子通道[2] 为例，选择性滤膜的孔径大小和分子组成决定了通道对钾离子的选择性[99-102]。钾离子、钠离子的原子半径分别为1.33Å和0.95Å [43]，尽管钠离子小于钾离子，但钾离子通道却能有效地选择钾离子通过，因为钾通道的离子通路外三分之一部分为选择性过滤器, 选择性过滤器决定了离子选择的特异性。钾通道有四个钾离子结合位点，而钠离子虽然小于钾离子，但无法与通道内衬的氧原子相作用，所以不能有效通过钾通道。同样，钠通道对钠离子的通透性比钾离子高12倍以上，钠离子经过孔道时会脱去大部分结合水，剩下的水分子会作为离子伴侣分子，帮助钠离子通过选择性过滤器，这个离子-水的复合体可以被用来选择钠离子而排除钾离子。

有文献表述，每20个钾离子通过该通道，就会有一个钠离子通过[103]；另一文献又是这样表述的，钾离子通道对钾的通透能力是钠离子的一千倍，即一千个通过的钾离子中只可能有一个钠离子混入[104]；还有文献提供了以下数据：Na+的离子半径（0.098 Å）虽然比K+的（0.133 Å）小很多，但其通透性不到K+的万分之一[105]。

同为生命科学教材，对同一个问题提供的数据之差别却如此悬殊，如Na+、 K+离子半径的差别，钾离子通透选择性的误差等，真是为难了学子们。我们折中一下，将钾离子通道对钠离子的通透率暂定为0.01～5%。尽管数据差别如此之大，但还是说明了这样的一个事实：离子通道的选择性不是绝对的。

膜电位对钾离子浓度的敏感性导致了胞内胞外钾浓度调节机理的进化，其中之一即为血脑屏障，限制了钾以及其它血液负载物进入脑部的胞外体液中，也包括其它的非必需阳离子，特别是金属离子。过量钾离子一旦突破血脑屏障，还可被星形胶质细胞突起的网络系统分散到一个更大的区域，这种星形胶质细胞调节胞内钾离子浓度的机理，被称为钾离子空间缓冲作用[106-108]。

以铜离子为例，在生理状态下，毛细血管会阻止其进入脑内。过量的铜离子会随着时间的推移，通过血液循环进入到脑血管中并沉积在血管壁上，尤其是在毛细血管的内皮细胞上，而这些细胞恰是大脑防御系统血脑屏障的关键成分，调控分子进出脑组织[109]。过量铜离子肯定突破了血脑屏障，否则无法解释脑组织中铜离子的来源问题，所以血脑屏障的通透选择性也是相对的。

阳离子入脑途径

阳离子能够通过血脑屏障、脉络丛和鼻腔被神经组织所吸收[110]。有些通道蛋白选择性较强，只允许一种离子通过；而另一些通道蛋白则允许几种具有相同化合价的同性离子通过；还有一些通道蛋白则完全是随机的[111]。

人体共有12对神经出入脑，只有嗅神经裸露在外[14]。嗅神经始于鼻腔的嗅粘膜，嗅细胞的中枢突先在粘膜内合并交织成丛，再由丛合成15～20条嗅丝。嗅丝离开嗅粘膜，向上穿经筛骨筛板的小孔进入颅前窝，终止于嗅球[112]。这也是为什么有些颅压增高病人会出现自鼻腔外漏脑脊液情况的原因。

帕金森病（PD）患者中脑黑质部位多巴胺能神经元变性死亡，可能与其长期暴露于挥发性物质或特殊环境有关，是由黑质在脑内所处的特殊位置及嗅神经裸露在外所决定的，一是黑质居于脑的中心位置，获得非必需阳离子的几率远大于脑的其它部位，二是与裸露在外的嗅神经关系直接。Ulla等[113] 通过MRI检查PD患者的黑质及尾壳核有明显的铁沉积，并且与运动症状的严重程度相关。嗅觉障碍是PD患者出现的第一个临床症状，早于运动症状出现，但易被患者与医生所忽视。又有研究显示，PD患者的晚期，约80%会进展为痴呆，即帕金森痴呆（PDD），严重的嗅觉障碍可以作为PDD渐近发展的重要临床指标[114]。

以上事实足以说明，非必需阳离子进入神经元胞内的途径可能不只是一种，因为是微量或非必需元素，生命进化过程中并没有为其留有专用通道和配备专用转运体。

阳离子在胞内位置

阳离子又称正离子，是指失去外层的电子以达到相对稳定结构的离子形式，无机多指过渡金属离子；有机阳离子多指向了大大小小的碳化合物分子，任何蛋白质都有一个特征性PH，称为等电点（PH=7时不带任何电荷），低于等电点时带有正电荷，可在胞内直接占钾位（见图4）。

非必需阳离子之所以能够“长途跋涉”游荡到中枢神经系统并侵入神经元内，是其游离状态的特性所决定。因为，更多同类阳离子，如锌约85%，在进入体内初始阶段即被截获，并与其它阴性物质结合而处于稳态，只有少数阳离子（锌约15%）在四处游荡，途中即使与其它阴性物质偶遇也是临时性的虚结合，不会真正处于“稳态”。

这样的阳离子，特别是金属离子，一旦进入神经元内，它的密度决定了它的着落点——沉淀在细胞膜内表面。进入胞内的阳离子参与了产生膜电位的活动，尽管其发挥的作用是消极的。细胞核也往往会被中央细胞器推挤到细胞的边缘，这又增加了金属离子再次闯进细胞核的概率，这也是为什么细胞核似乎是大多数金属离子攻击的靶点的主要原因之一，进入胞核的后果则是导致基因突变或癌变。Luckey[115] 就认为细胞核似乎是大多数致癌金属的主要靶子，并举出Heath发现致癌金属主要存在核内作为例证。

图4 蛋白质等大分子通过它们表面上互补的电荷而相互结结合

极性共价键分子间存在着相对较弱静电吸引力。任何含有许多极性基团的大分子，其表面一定有部分区域带正电而另一部分带负电。当这样分子遇到另一个带异性电荷分子时，通过静电吸引力而相互吸引，当两个大分子表面形成大量非共价键时，就会特异性地黏附在一起。还有，不带电荷的极性侧链也不能忽视，如在中性PH时，尽管酰胺的N不带电荷，但它是极性的。

阳离子进入细胞核、细胞器后，我们可认为已经处于“稳态”，可理解成“金属离子库”，处于游离状态的阳离子多沉淀在膜内表面，并参与了膜电位的活动。非必需阳离子，能突破血脑屏障已有难度，再次逃过离子通道的筛查闯入胞内，属难上加难。进入胞内的阳离子，再次闯入细胞核或细胞器内的概率，理论上与其逃离胞内的概率之低的程度几近相同，尽管如此，还是增加了其攻击细胞核的几率。金属离子转运体（DMT1），存在于脑内多种神经元细胞膜表面，为多种二价金属离子所共享，可转运Fe2+、Zn2+、Mn2+、Co2+、Cd2+、Cu2+、Ni2+、Pb2+等。尽管如此，进入细胞内的非必需金属离子一旦过量，DMT1的转运能力将无法满足实际需要而变得异常活跃。非必需阳离子进入胞内只有占钾位方能发挥其破坏作用，不存在占位钠离子、钙离子的情况，即使有此情况发生，也没有实质性意义。

另外，阳离子堵塞或破坏离子通道。内向整流类K+通道是Kv或Shaker类通道的另一种形式，这种整流现象是细胞内带正电荷的Mg2+、Spd在细胞膜去极化时堵塞了离子孔道使外向钾电流缺失所致[116,117]。在生理条件下，多胺以带正电荷多聚阳离子状态存在，多胺可以嵌入膜上的离子通道，阻止离子向胞内外的运输，特别是多胺对Ca2+和K+通道的阻塞或干扰，如所有的钾离子通道都可以被TEA阻断[118,119]，对细胞信号的传递过程会产生显著影响[120-125]，相当于间接占据了钾位。TEA可以在膜两侧以不同的位点和通道结合进而阻断钾通道[4,6,8,56,126]。

血脑屏障与离子通道，其通透性与选择性不是绝对的，这也包括离子通道的门控方式。离子通道的另一个重要性质就是门控，拥有此性质的通道可开放和关闭。由于神经元胞膜存在着孔道，胞外液的金属离子，只要它的体积小于孔道的孔径，都易于扩散或随着内流离子而混入胞内，不论是以什么形式及脂溶与否。

最近，Scientific American报导了Thomas Heimburg等科学家的研究，认为神经元之间通过类似于声波的机械波通信，而电脉冲只是这个过程的副产品。确实，将动作电位的传导方式理解成机械波也没有什么不妥之处，因为声光电磁力热的能量是可以相互转换的，最终都可能转化成机械力使离子通道的构形发生改变。

钾离子与钾通道

对细胞神经生物学而言，特别重要的离子有单价阳离子钠和钾，二价阳离子钙以及单价阴离子氯。其中钾离子，是由钾原子失去最外层的一个电子得到的离子，是细胞内液的主要阳离子，体内98%的钾存在于细胞内。正常情况下，日常饮食中的钾含量足以满足机体需要，不会出现缺钾。钾离子在细胞内外不同浓度的分布是形成胞膜负电位的一个重要原因。钾离子通道还参与调节各种细胞的电活动并决定着动作电位的发放频率、幅值和重复放电活动的模式。

简单地说，反应细胞生死存亡的一个客观指标就是判断该细胞是否还存在着细胞膜负电位，所以钾离子和钾离子通道的重要性是不言而喻的，也可理解成是动作电位产生与发放的起点与终点。

那么，钾通道究竟是如何实现其选择性通透机制的呢？这源自于链霉菌的钾通道（KcsA钾通道）的结构研究，它具有和其它钾通道相似的氨基酸序列[101,102,127,128]，尤其是位于膜内包含钾通道特征序列的孔区部分具有和果蝇shaker通道以及脊椎动物电压门控钾通道几乎相同的序列[129,130]。通过研究KcsA钾通道与真核生物钾通道毒素的相互作用，证实了它的孔区与真核生物孔区相似，并且这种构象在通道与膜分离的情况下仍然不变[131]。KcsA钾通道结构与对shaker通道功能与突变的研究结果相一致，其孔区概念是依据蝎毒与通道的作用研究定义的[132]，这种抑制剂与孔道膜外氨基酸残基互相发生作用[133,134]。

当钾离子通道因外力损伤或基因突变导致门控选择性降低时，将会有大量钠离子从钾通道提前“混”入胞内，之后再被钠-钾泵转至胞外。钠离子若以此方式占据钾位对神经元进行破坏[42]，其行为是十分隐蔽的，虽然与铜、锌等同为阳离子，但不易被觉察。无一例外，所有钾通道都具有一个关键的氨基酸序列，即钾通道的特征序列。对该序列内的氨基酸进行突变，将会使钾通道丧失区分钾离子和钠离子的能力[7,42,126]，导致钠和钾离子一样能通过通道。

Yuh-Nung Jan和Lily Yeh Jan揭示了shaker突变体的钾通道异常。钾通道异常受损，钠通透性提高会导致神经元膜电位负值减小，最终导致神经元过早凋亡[135,136]。钾通道一旦受损，即使没有非必需阳离子如铜、锌、铝、铁等离子的参与，同样会引起神经元的过早凋亡，此时是提前进入的钠离子与钾离子产生了竞争性占位。钾通道的重要性由此可窥见一斑。

离子泵

在细胞神经生理学中，有两种离子泵尤其重要：钠-钾泵、钙泵，都是酶。钠-钾泵的作用使膜内钠离子与膜外钾离子交换，确保钾离子富集于神经元内，钠离子富集于神经元外[137-139]；钙泵则将钙离子从胞内跨膜转运至胞外[140-142]。离子泵的作用是形成离子浓度梯度，需要消耗代谢能量[143-147]。据估计，人脑消耗了全身能量的20%，而钠-钾泵又消耗了人脑能量的70%。

离子泵与癫痫

动作电位的幅值与膜电位的负值呈正相关。非必需阳离子胞内占位缩短了动作电位发生和膜复极化的时程，无效动作电位发放频率增高，可诱发癫痫。

事实上，AD患者比同龄阶段不患该病的人群发生癫痫的概率高出10倍以上[148]。Nelson等[149] 研究表明，老年斑和神经原纤维缠结同样存在颞叶癫痫中，淀粉样斑块的首次描述和命名源于癫痫患者。Palop等[150] 将人淀粉样前体蛋白（hAPP）基因植入小鼠脑内，用视频脑电监测到小鼠海马和皮质频繁发放尖波、棘波，尤其在hAPP和Aβ沉积的大脑部位，小鼠还会间断出现与海马相关的单纯部分性发作和复杂部分性发作。Scarmeas等[151] 发现，AD是癫痫发作独立危险因素，AD患者的癫痫发病率高于普通人群；A-matniek等[152] 发现发病年龄较小的AD患者在病程初期即可出现癫痫发作。Scharfman[153] 发现，海马硬化可以导致神经元丢失，但对齿状回神经元影响较小，最终导致该部位兴奋性神经元的数目和功能大于抑制性神经元的数目和功能，干扰了电活动的平衡。Hall等[154] 研究发现，海马神经元的树突过度兴奋而表达过量的Aβ，这种树突的过度兴奋与Kv4.2的缺失有关。抗癫痫药物左乙拉西坦可以阻止Kv4.2通道的缺失，在AD伴癫痫患者治疗中对认知功能的改善具有重要意义[154]。

离子泵与癌症

当机体的组织生长及自我更新时，细胞必须维持其合适的特定性质，必须占据其合适的位置，不能侵入到它不该去的地方。当一个细胞违背其基本准则时，潜在的灾难性故障就会发生。

癌症的发生，就是这样的故障：无视正常的约束增殖，侵入其它细胞领地。以铜离子为例，我们设定细胞内铜离子小于或等于10个为正常，假如实际侵入100个，经过4次分裂后就已降至正常水平，降低了非必要阳离子的浓度，只要及时切断铜离子源，此时的瘤应是良性的。正常体细胞分裂次数约50次，有时人的生理承受能力是坚持不到50次裂变的。这期间若发生如下事件就会发生癌变，即良性瘤变成恶性瘤：一是钾离子通道遭到铜离子破坏，如Shaker突变体的产生，钠离子大量通过钾通道流入胞内占据钾位，严重消减膜电位；二是无效动作电位高频发放，钠-钾泵过量消耗ATP释放的能量；三是铜离子侵入细胞核引起DNA碱基序列改变致使细胞无约束增殖。体细胞不同于神经元，成熟的中枢神经元作为高度特化的细胞不再具备分裂增殖能力。

发生如此情况，即使在癌细胞内检测不到超标的铜离子，钠离子也会替代铜离子占据钾位而继续作乱，不断分裂增殖的细胞会与正常细胞在能量、生存空间等方面产生竞争。应用本文这一观点，还可合理解释海勒（HeLa）细胞 “永生”的原因，可能是Shaker突变体导致钾离子通道受损、细胞核DNA碱基序列改变以及培养液中的钠离子提前占钾位所致[105]。

事实上，外在因素只能对一小部分引发的癌症突变负责。在人的一生中，机体约发生1016细胞分裂，因此每个单独基因都可能在超过109细胞分裂时遭受突变。从这个角度来看，癌的问题似乎不是它为什么会发生，而是它发生的为什么会这么稀少了。其实，癌症与AD、PD、癫痫、心律失常一样，同属于离子通道病，癌细胞的本性可能并不“恶”，它的增殖、侵袭及转移是其为了躲避阳离子占位的伤害而不想死亡的一种应激反应，是“从善”意愿的N次表达，遗憾的是我们并没有认真地聆听它的“声音”。

Aβ蛋白、斑点及斑块

1984年，Glenner和Wong[155] 从老年斑内纯化和分离得到了Aβ并解读得到其蛋白序列。正常情况下，中枢神经系统内的Aβ主要由神经元产生，通过吞噬细胞的吞噬、酶降解、受体转导等途径清除[156]。后来研究发现，激活状态下的星形胶质细胞也可以产生Aβ。在AD中，活化的星形胶质细胞会聚集在老年斑周围[157,158]。

星形胶质细胞还可以摄取和内化细胞外环境中的Aβ [159-161]。例如在AD患者大脑中的星形胶质细胞内能检测到 Aβ [162]，将星形胶质细胞培养在含有Aβ的AD小鼠脑片上，发现星形胶质细胞能和老年斑结合并且能够减少这些脑片中总的Aβ含量[163,164]。星形胶质细胞还能够分泌多种炎症因子，特别是小胶质细胞，被认为是脑实质中唯一的免疫细胞[162]。

我们研究的结果，支持了 Aβ是所有神经系统所有细胞APP代谢的正常产物的观点，认为淀粉样斑点是脑细胞异常凋亡后的遗骸，淀粉样斑块是淀粉样斑点之间通过范德华力、静电吸引力聚集而成，间质为淀粉样蛋白。脑细胞依次包含神经元、小胶质细胞、星形胶质细胞，其遗骸形成斑点的核多为阳离子，无核遗骸多能被胶质细胞吸收、消化和转运，此间，自噬也是细胞的选项之一。

淀粉样斑点的形成与珍珠的生成有相似之处，淀粉样斑块的形成又类似于珊瑚，珊瑚是由无数个珊瑚虫遗骸堆积而成。我们由此推测，正常人脑中也会有数以亿计的“斑点”，可能会像夜空中的繁星一样，闪烁着金色的“光芒”。

我们还认为，在AD 的病理生理过程中，Aβ沉积是机体的一种保护性机制，而小胶质细胞释放炎症因子，则是为保护神经组织的应激反应。所以，刻意清除这样的“斑点”与“斑块”，可能无实际意义甚或得不偿失。

在新药研制方面，一种用于清除AD患者脑内淀粉样蛋白斑块的疫苗虽然在清除斑块上十分有效，但却不能阻止由该疾病引起的神经系统的退化，疫苗可以减少甚至完全清除斑块，但患者症状并未得到相应的改善。Lawrence Steinman等[165] 研究显示，尽管一些淀粉样蛋白的片断（包括tau蛋白和朊蛋白）也会形成纤维，但这些纤维能够快速缓解小鼠的神经退行性症状，某些情况下Aβ是有益的。已有临床病理研究发现，部分脑内老年斑广泛存在的人群并无痴呆表现。

有关AD的解决方案

本文的核心观点认为，非必需阳离子在胞内占钾位，是AD发病的初始因素。若此，解决AD方案应从预防与治疗二方面入手，预防的外因在环境，尤其是重金属离子，内因则是身体酸碱度，酸性体质细胞内蛋白质带正电荷；治疗应首选物理手段，尤其是经颅磁电（微磁弱电）刺激技术，其最佳靶点是电压门控钙离子通道，其次是将胞内过量阳离子激荡出胞外，目的是从根本上阻断神经元凋亡程序，激活递质能神经元。阳离子对电磁场高度敏感，针对由兴奋转入抑制状态的神经元的再次激活，常规的化学手段会力所不及，此类疾病应划为物理病。

目前，化学手段的主攻方向多是将治疗的靶点锁定在淀粉样斑块或炎症因子上，这可能不是明智的选择，如金属离子螯合剂、寡糖类炎性抑制剂、硫胺素（维生素B1）等，其实际效果不会强于AD辅助用药胆碱脂酶抑制剂、谷氨酸受体拮抗剂等。

金属离子螯合剂是一类通过螯合金属离子形成稳定的水溶性络合物的一类有机或无机化合物[166-168]，首先要能通过血脑屏障的筛查，如脂溶性的小分子化合物，其次还要求相应的金属离子只能具有较低的亲合力，否则会破坏机体的离子稳态和正常功能[169,170]，同时还应该具有无毒高效且易排出体外的特性[171]，这些条件十分苛刻，目前研究比较多的是氯碘羟喹（CQ）[172]，对胞内金属离子不会产生影响；炎性抑制剂，是基于小胶质细胞的免疫反应所释放出的炎症因子，如前所述这样的炎症因子也许有益无害，若必须加以抑制，只需服用非激素类抗炎药物即可。流行病学资料表明，长期应用非激素类抗炎药可降低AD的发病率，减少患病风险达60～80%。非激素抗炎药物可降低小胶质细胞的活性，如布洛芬可显著降低Tg2576鼠Aβ老年斑和脑内Aβ水平[14]，不同非激素类抗炎药物应用于APP鼠也获得了类似效果；还有应用寡糖类分子捕猎淀粉样蛋白以消除脑内Aβ，有学者明确指出，这样的“糖丸”吃与不吃都一样。

另外，有研究者将超声波作为打开血脑屏障的一种手段，因此而引发的后果——对无辜神经元的伤害及血脑屏障的破坏，可能会因小失大；脑深部电刺激术（DBS），高强度重复经颅磁（rTMS）刺激等，若处理不当则相当于脑毁损术，其过失不仅仅是患者的灾难，对医学科学的发展更会造成恶劣影响，医学的最高原则是no harm，不能因为治疗而带来附加伤害[1]。神经元和血脑屏障更需要的是保护，不是所有的物理手段都可以用来治疗脑病的。

AD、PD临床试验

我们研究组对80例轻中度AD患者进行了双中心、随机、双盲、平行、安慰剂对照8周临床试验，其中治疗组和对照组各40例，试验结果证明：经颅磁电脑病治疗仪治疗轻中度AD具有效果，对患者的精神状态、认知行为和日常生活自理能力有较好的改善作用[173,174]（见表1）。

我们研究组还对22例轻中度PD患者，采用双中心、随机、双盲、自身交叉对照法进行了20天临床观察，试验结果证明：经颅磁电脑病治疗仪可明显改善PD患者的静止性震颤、僵直、运动迟缓等症状，且使用安全[175,176]（见表2）。

以上结论数据，分别被国家药监部门认可，并作为认证注册帕金森治疗仪（2011年）、阿尔茨海默治疗仪（2014年）部分临床依据。

表1 治疗组与对照组, 治疗8周（治疗后-治疗前）后各量表差值

评分结果(ｘ±ｓ,分)、检验统计量（t值）及P值

组别 例数 MMSE ADAS CDR ADL

治疗组 40 1.58±1.53 -1.78±1.68 -0.14±0.32 1.63±3.47

对照组 40 0.28±1.45 -0.03±1.53 -0.04±0.17 0.00±3.00

检验统计量 3.895 -4.812 -1.734 2.242

P 0.0002 < 0.0001 0.0880 0.0278

表2 两组患者不同阶段临床疗效总显效率与总有效率比较(PPS 和 FAS)

分组	治疗 10 天后	治疗 20 天后	P1 值	P2 值
例数	总显效率	总有效率	例数	总显效率	总有效率
A组	11	45.45%	72.73%	11	36.36%	81.82%	0.0351	0.0010
B组	11	0.00	0.00	11	18.18%	45.45%	0.6351	0.1827

注：P1：总显效率的卡方检验；P2：总有效率的卡方检验；P 值：上行为治疗 10 天后分析结果，下行为治疗20天后分析结果。

癫痫鼠动物试验

本研究组也探讨了经颅磁电刺激疗法对海仁酸致颞叶癫痫鼠的疗效[177-183]。62只大鼠按照随机数字表法分为预处理组(共32只)和治疗组(共30只)，预处理组再分为4个小组，治疗组再分为3个小组，每组10只。共进行了14 d的刺激观察，记录并比较3组大鼠行为学、电生理学及组织学变化，以评估经颅磁电刺激疗法对癫痫大鼠的疗效。

结果与结论：50%MCI为最佳刺激强度。癫痫刺激组大鼠癫痫波出现的频率明显低于癫痫非刺激组大鼠[(30.210 ±4.580)次/min vs.(31.380 ± 4.247)次/min]，差异有统计学意义(t=3.235，P=0.001)。Timm染色结果提示3组大鼠染色评分差异有统计学意义(F=17.429, P=0.000)，癫痫刺激组大鼠海马齿状回的内分子层Timm染色评分较癫痫非刺激组明显减轻，差异有统计学意义(P＜0.05)。经颅磁电刺激疗法可通过改善癫痫大鼠海马齿状回内分子层组织学变化程度来影响齿状回神经元环路的形成，进而降低癫痫脑电波的发作频率（见表3及图5、图6）。

表3 不同电流强度磁电刺激预处理后大鼠痫性发作程度评分

A组	只数	癫痫发作评分	平均秩次
0	1	2	3	4	5
A1(0%MCI)	8	0	0	0	0	3	5	26.190
A2(25%MCI )	8	0	0	0	3	3	2	20.380
A3(50%MCI )	8	0	2	4	1	1	0	7.750
A4(75%MCI )	8	0	0	3	4	1	0	11.690

H=19.992，P=0.000；MCI：最大电流强度。

图5 经颅磁电治疗后Wistar大鼠脑电表现

A：对照组；B：癫痫非刺激组；C：癫痫刺激组；*为癫痫波

图6 大鼠经颅磁电刺激14 d后海马齿状回Timm染色结果(100)

A：对照组；B：癫痫非刺激组；C：癫痫刺激组；黑色箭头所示为染色带。在给予癫痫大鼠TMES治疗14 d后，我们用Timm评分来评价TMES对MFS的影响程度。结果发现对照组的大鼠海马齿状回无Timm染色带出现，而癫痫非刺激组大鼠在海马齿状回的内分子层表现出较黑色的Timm染色带，癫痫刺激组大鼠海马齿状回的内分子层Timm染色程度较癫痫非刺激组明显减轻。

经颅磁电刺激精准性

综合PD、AD临床试验、癫痫鼠动物试验的结果，我们研究认为，经颅磁电刺激技术主要是阻断了神经元的凋亡程序，其作用的靶点是电压门控钙离子通道，激活了递质能神经元，而外加特定脉动电磁场又活化了金属阳离子共享转运体DMT1，增加了神经元内非必需阳离子荡出胞外的几率，同时也消除了炎性反应等。

我们还分析认为，经颅磁电刺激技术，之所以能够做到精准激活异常神经元而不干扰正常神经元，是因为正常神经元释放神经递质需要满足以下条件：① 有可释放的神经递质，内源性神经递质的生成需要过程和时间；② 神经递质装入囊泡及囊泡转运需要过程和时间；③ 要有钙离子内流，内流钙离子的数量与突触间隙钙离子浓度密切相关；④ 突触间隙兴奋与抑制二类神经递质要有保持平衡的需要[184-187]。

外加脉动电磁场对于不具备上述条件的正常神经元做的是“无用功”，而对于已经具备了上述条件的正常神经元，即使没有外加电磁场的刺激，凭借其自身所产生的动作电位也会自然激活电压门控钙离子通道。

结论

本文核心观点可视为探讨散发性AD病因学说，是脑细胞激活论姊妹篇，脑细胞激活论是对AD等神经元退行性变疾病治疗方法与治疗机理的阐释，适用于脑病又不局限于脑病，解决AD方案应从预防与治疗二方面入手，预防的外因在环境，尤其是重金属离子，内因则是身体酸碱度；治疗应首选物理手段，尤其是经颅磁电刺激技术。

[参考文献] (References)

[1] Sun Z D. The Theory of Brain Cell Activation[J]. Journal of US-China Medical Science, 2017, 14(5), 203-211.
[2] Neyton J, Miller C. Discrete Ba2+ block as a probe of ion occupancy and pore structure in the high-conductance Ca2+ -activated K+ channel[J]. J Gen Physiol, 1988, 92(5): 569-586.
[3] Armstrong C M, Binstock L. Anomalous Rectification in the Squid Giant Axon Injected[J]. Journal of General Physiology, 1965, 48(5): 859-872.
[4] Armstrong C M, Hille B. The Inner Quaternary Ammonium Ion Receptor in Potassium Channels of the Node of Ranvier[J]. Journal of General Physiology, 1972, 59(4): 388.
[5] Mackinnon R, Yellen G. Mutations affecting TEA blockade and ion permeation in voltage- activated K+ channels[J]. Science, 1990, 250(4978): 276-279.
[6] Yellen G, Jurman M, Abramson T, et al. Mutations affecting internal TEA blockade identify the probable pore-forming region of a K+ channel[J]. Science, 1991, 251(4996): 939-942.
[7] Heginbotham L, Abramson T, MacKinnon R. A functional connection between the pores of distantly related ion channels as revealed by mutant K+ channels[J]. Science, 1992, 258 (5085): 1152-1155.
[8] Liu Y, Holmgren M, Jurman M E, et al. Gated Access to the Pore of a Voltage-Dependent K+ Channel[J]. Neuron, 1997, 19(1): 175-184.
[9] Dong J, Jia J P. Exploring the etiology hypothesis of sporadic Alzheimer's disease from a genetic perspective[A]. Compilation of the 4th National Symposium on Dementia and Cognitive Impairment and Advanced Lectures[C], 2015.
[10] Kerr M L, Small D H. Cytoplasmic domain of the β-amyloid protein precursor of Alzheimer\"s disease: Function, regulation of proteolysis, and implications for drug development[J]. Journal of Neuroscience Research, 2005, 80(2): 151-159.
[11] Nistor M, Don M, Parekh M, et al. Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain[J]. Neurobiology of Aging, 2007, 28 (10): 1493-1506.
[12] Lott I T, Head E. Alzheimer disease and Down syndrome: factors in pathogenesis[J]. Neurobiology of Aging, 2005, 26(3): 383-389.
[13] ALZHEIMER'S ASSOCIATION. 2015 Alzheimer's disease facts and figures[J]. Alzheimers Dement, 2015, 11(3): 332-348.
[14] Han J S. Neuro Science (The third edition) [M] .Beijing: Peking university medical press, 2009.
[15] Zhao B L, Wan L. Metabolic imbalance of metal ions and early pathogenesis of Alzheimer's disease[J]. Progress in Biochemisry and Biophysics, 2012, 39(8): 756-763.
[16] Laferla F M, Tinkle B T, Bieberich C J, et al. The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice[J]. Nature Genetics, 1995, 9 (1): 21.
[17] Jana A, Pahan K. Fibrillar amyloid-bcta peptides kill human primary ncurons via NADPH oxidase-mediated activation of neutral sphingomy-clinase. Implications for Alzheimer's disease[J]. J Biol Chem, 2004, 279(49): 51451-51459.
[18] Yang X H, Jiang Z F. Activation of microglia and Alzheimer's disease[J]. Chemistry of Life, 2007, 27(6): 548-550.
[19] Zhu Y B, Lu P H, Sheng Z H. A New Exploration of the Pathogenesis of AD: Hypothesis of Axoplasmic Transport Obstacles[J]. Progress in Physiological Sciences, 2008, 39(1): 5-9.
[20] Luo H B, Shi X Q, Li Y, et al. The expression of endoplasmic reticulum A beta binding protein and the effect of stilbene glycoside in behavioral disorders induced by A beta in rats[J].Journal of Apoplexy and Nervous Diseases, 2013, 30(2):128-131.
[21] Qi J, Peng J X. Degradation of endoplasmic reticulum-related proteins and its mechanism[J]. Chinese Journal of Cell Biology, 2004, 26(2):103-107.
[22] Lee M H, Siddoway B, Kaeser G E, et al. Somatic APP gene recombination in Alzheimer's disease and normal neurons[J]. Nature, 2018, 563: 639-645.
[23] Anand R, Gill K D, Mahdi A A. Therapeutics of Alzheimer's disease: Past, present and future[J] . Neuropharmacology, 2014.
[24] Schmitz C, Rutten B P F, Pielen A, et al.Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease[J]. American Journal of Pathology, 2004, 164(4): 1495-1502.
[25] Williams D R. "Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau"[J]. Internal Medicine Journal, 2006, 36 (10): 652-60.
[26] Nie J, Shi J S. The role of presenilin in the pathogenesis of Alzheimer's disease[J]. West china journal of pharmaceutical sciences, 2017,32(1): 99-103.
[27] Edlund C, SöDerberg M, Kristensson K. Isoprenoids in aging and neurodegeneration[J]. Neurochemistry international, 1994, 25(1): 35-38.
[28] Bu G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways,pathogenesis and therapy[J]. Nat Rev Neurosci, 2009,10(5): 333-334.
[29] Bu G, Liu C C, Takahisa K. Vascular hypothesis of Alzheimer's disease: role of apoE and apoE receptors[J]. Molecular Neurodegeneration, 2013, 8(Suppl 1): O20-O20.
[30] Finch C E, Morgan T E. Systemic Inflammation, Infection, ApoE Alleles, and Alzheimer Disease: A Position Paper[J]. Current Alzheimer Research, 2007, 4(2): 185-189.
[31] Ashford J W. Treatment of Alzheimer's Disease: The Legacy of the Cholinergic Hypothesis, Neuroplasticity, and Future Directions[J]. Journal of Alzheimers Disease, 2015, 47(1): 149-156.
[32] Fitzgerald R S, Shirahata M, Ide T, et al. The cholinergic hypothesis revisited-an unfinished story[J]. Biological Signals, 1995, 4(5): 298-303.
[33] Meraz-Ríos M A, Danira T R, Diana F B, et al. Inflammatory process in Alzheimer's Disease[J]. Frontiers in Integrative Neuroscience, 2013, 7: 59.
[34] Frank-Cannon T C, Alto L T, Mcalpine F E, et al. Does neuroinflammation fan the flame in neurodegenerative diseases?[J]. Molecular Neurodegeneration, 2009, 4(1): 47.
[35] Perry V H, Nicoll J A R, Holmes C. Microglia in neurodegenerative disease[J]. Nature Reviews Neurology, 2010, 6(4): 193-201.
[36] Rotshenker S. The role of galectin-3/mac-2 in the activation of the innate-immune function of phagocytosis in microglia in injury and disease[J]. Journal of Molecular Neuroscience, 2009, 39: 99-103.
[37] Kaur G, Han S J, Yang I, et al. Microglia and central nervous system immunity[J]. Neurosurgery Clinics of North America, 2010, 21(1): 43-51.
[38] Luo Y F, Zhang J, Liu N Q, et al. Copper ions influence the toxicity of β-amyloid (1-42) in a concentration-dependent manner in a Caenorhabditis elegans model of Alzheimer' s disease[J].Sei China Life Sci, 2011, 54(6): 527-534.
[39] Hodgkin A L, Huxley A F. A quantitative description of membrane current and its application to conduction and excitation in nerve[J]. Physiol, 1952, 117: 500.
[40] Hodgkin A L, Huxley A F, Katz B. Measurement of current-voltage relations in the membrane of the giant axon of Loligo[J]. The Journal of Physiology, 1952, 116(4): 424-448.
[41] Hodgkin A L, Huxley A F. A quantitative description of membrane current and its application to conduction and excitation in verve[J]. The Journal of Physiology, 1952, 117 (4): 500-544.
[42] Bear M F. Neuroscience: Explore the brain (Second Edition) [M]. Beijing: Higher Education Press, 2004.
[43] Doyle D A, Morais Cabral J, Pfuetzner R A, et al. The Structure of the Potassium Channel: Molecular Basis of K+ Conduction and Selectivity[J]. Science, 1998, 280(5360): 69 -77.
[44] Nicholls J G, Robert Martin A, Fuchs P A, et al. From Neuron To Brain (Fifth edition) [M]. England: Sinauer Associates Is an Imprint of Oxford Un, 2011.
[45] Alberts B, Bray D, Hopkin K, et al. Essential Cell Biology(Third Edition)[M]. Boca Raton: CRC Press Inc, 2009.
[46] Nuttall JR, Oteiza PI. Zine and the aging brain[J]. Genes Nutrit, 2014, 9(1): 1-11.
[47] Luo Y F, Zhang J, Liu N Q, et al. Copper ions influence the toxicity of β-amyloid(1- 42) in a concentration-dependent manner in a Caenorhabditis elegans model of Alzheimer's disease[J]. Sci China Life Sci, 2011, 54(6): 527-534.
[48] Faller P, Hureau C. Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-beta peptide[J]. Dalton Trans, 2009, (7): 1080-1094.
[49] Hung Y H, Bush A I, Cherny R A. Copper in the brain and Alzheimer's disease[J]. J Biol Inorg Chem, 2010, 15: 61-76.
[50] Himes R A, Park G Y, Siluvai G S, et al. Structural studies of copper (I) complexes of amyloid-beta peptide fragments: formation of two-coordinate bis(histidine) complexes[J]. Angew Chem Int Ed Eng1, 2008, 47: 9084-9087.
[51] Danscher G, Jensen K B, Frederickson C J, et al. Increased amount of zinc in the hippocampus and amygdala of Alzheimer's diseased brains: a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material[J]. J Neurosci Methods, 1997, 76(1): 53-59.
[52] Cornett C R, Markesbery W R, Ehmann W D. Imbalances of trace elements related to oxidative damage in Alzheimer's disease brain [J]. Neurotoxicology, 1998, 19(3):339-345.
[53] Deibel M A, Ehmann W D, Markesbery W R. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress [J]. J Neurol Sci, 1996, 143(1-2): 137-142.
[54] Ehmann W D, Markesbery W R, Alauddin M, et al. Brain trace elements in Alzheimer's disease[J]. Neurotoxicology, 1986, 7(1): 195-206.
[55] Samudralwar D L, Diprete C C, Ni B F, et al. Elemental imbalances in the olfactory pathway in Alzheimer's disease[J]. J Neurol Sci, 1995, 130(2): 139-145.
[56] Wenstrup D, Ehmann W D, Markesbery W R. Trace element imbalances in isolated subcellular fractions of Alzheimer's disease brains[J]. Brain Res, 1990, 533(1): 125-131.
[57] Lovell M A, Robertson J D, Teesdale W J, et al. Copper, iron and zinc in Alzheimer's disease senile plaques[J]. J Neurol Sci, 1998, 158(1):47-52.
[58] Dong J, Atwood C S, Anderson V E, et al. Metal binding and oxidation of amyloid-β within isolated senile plaque cores: Raman microscopic evidence[J]. Biochemistry, 2003, 42 (10): 2768-2773.
[59] Religa D, Strozyk D, Cherny R A, et al. Elevated cortical zinc in Alzheimer disease [J]. Neurology, 2006, 67(1): 69-75.
[60] Zhang L H, Wang X, Zheng Z H, et al. Altered expression and distribution of zinc transporters in APP/PS1 transgenic mouse brain[J]. Neurobiol Aging, 2010, 31(1): 74-87.
[61] Zheng W, Wang T, Yu D, et al. Elevation of zinc transporter ZnT3 protein in the cerebellar cortex of the AβPP/PS1 transgenic mouse[J]. J Alzheimers Dis, 2010, 20(1): 323 -331.
[62] Friedlich A L, Lee J Y, van Groen T, et al. Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer's disease[J]. J Neurosci, 2004, 24(13): 3453-3459.
[63] Cuajungco M P, Faget K Y. Zinc takes the center stage: its paradoxical role in Alzheimer's disease[J]. Brain Res Brain Res Rev, 2003, 41(1): 44-56.
[64] Bjorkdahl C, Sjogren M J, Winblad B, et al. Zinc induces neurofilament phosphorylation independent of p70 S6 kinase in N2a cells[J]. Neuroreport, 2005, 16(6): 591-595.
[65] Suh S W, Jensen K B, Jensen M S, et al. Histochemically-reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer's diseased brains[J]. Brain Res, 2000, 852(2): 274-278.
[66] Yokoyama M, Koh J, Choi D W. Brief exposure to zinc is toxic to cortical neurons[J]. Neurosic Lett, 1986, 71(3): 351-355.
[67] Lutsenko S, Bhattacharjee A, Hubbard A L. Copper handling machinery of the brain[J]. Metallomics, 2010, 2: 596-608.
[68] Wang H Q, Hu H T. Copper and Alzheimer's disease[J]. Foreign Medical Sciences (Section of Medgeography), 2008, 29(2): 57-59.
[69] Maynard C J, Cappai R, Volitakis I, et al. Overexpression of Alzheimer's Disease Amyloid-Opposes the Age-dependent Elevations of Brain Copper and Iron[J]. The Journal of Biological Chemistry, 2002, 277: 44670-44676.
[70] Huang X D, Cuajungco M P, Atwood C S, et al. Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity[J]. The Journal of Biological Chemistry, 1999, 274: 37111-37116.
[71] Lovel M A, Robertson J D, Teesdale W J, et al. Copper, iron and zinc in Alzheimer's disease senile plaques[J]. J Neurol Sci, 1998, 158(1): 47-52.
[72] Wang Z H, Li L. Copper and Alzheimer's disease[J]. Foreign Medical Sciences (Geriatrics), 2005, 26(5):205-208.
[73] Virk S A, Eslick G D. Aluminum Levels in Brain, Serum, and Cerebrospinal Fluid are Higher in Alzheimer's Disease Cases than in Controls: A Series of Meta-Analyses[J]. J Alzheimers Dis, 2015, 47(3): 629-638.
[74] Que E L, Domaille D W, Chang C J. Metals in neurobiology: probing their chemistry and biology with molecular imaging[J]. Chem Rev, 2008, 108(5): 1517-1549.
[75] Crapper D R, Krishnan S S, Dalton A J. Brain aluminum distribution in Alzheimer's disease and experimental neurofi brillary degeneration[J]. Science, 1973, 180: 511-513.
[76] Perl D P, Brody A R. Alzheimer's disease: X-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons[J]. Science, 1980, 208: 297-299.
[77] Yumoto S, Kakimi S, Ohsaki A, et al. Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer's disease[J]. J Inorg Biochem, 2009, 103: 1579-1584.
[78] González-Domínguez R, García-Barrera T, Gómez-Ariza J L. Homeostasis of metals in the progression of Alzheimer's disease[J]. Biometals, 2014, 27: 539-549.
[79] Cheng S Z, Wang X M, Liu H, et al. Experimental study on the pathogenesis of aluminum-induced Alzheimer's disease model rats[J]. Journal of Apoplexy and Nervous Diseases, 2012, 29(1): 41-43.
[80] Zhu W Z, Zhong W D, Wang W, et al. Quantitative MR phase-corrected imaging to investigate increased brain iron deposition of patients with Alzheimer disease[J]. Radiology, 2009, 253(2): 497-504.
[81] Brar S, Henderson D, Schenck J, et al. Iron accumulation in the substantia nigra of patiaents with Alzheimer disease and parkinsonism[J]. Arch Neurol, 2009, 66: 371-374.
[82] Xiao F, Li X G, Zhang X Y, et al. Combined administration of D-galactose and aluminum induces Alzheimer like lesions in brain[J]. Neurosci Bull, 2011, 27: 143-155.
[83] Kawahara M, Kato M, Kuroda Y. Effects of aluminum on the neurotoxicity of primary cultured neurons and on the aggregation of β-amyloid protein[J]. Brain Research Bulletin, 2001, 55(2):211-217.
[84] Walton J R, Wang M X. APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer's disease[J]. J Inorg Biochem, 2009, 103(11): 1548-1554.
[85] Justin Thenmozhi A, William Raja T R, Manivasagam T, et al. Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer's disease[J]. Nutr Neurosci, 2017, 20(6): 360-368.
[86] Rodella L F, Ricci F, Borsani E, et al. Aluminium exposure induces Alzheimer's disease-like histopathological alterations in mouse brain[J]. Histol Histopathol, 2008, 23 (4): 433.
[87] Xie Q, Xu H X, Liu Z, et al. T2map imaging study of rat Alzheimer's disease model[J]. Chinese Journal of Medical Imaging Technology, 2010, 26(s1): 114.
[88] Hutchinson R W, Cox A G, McLeod C W, et al. Imaging and spatial distribution of beta- amyloid peptide and metal ions in Alzheimer's plaques by laser ablation-inductively coupled plasma-mass spectrometry[J]. Anal Biochem, 2005, 346(2): 225-233.
[89] Sparks D L, Schreurs B G, Trace amounts of copper in water induce β-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease[J]. J Proc Natl Acad Sci, 2003, 100: 11065-11069.
[90] Wang Z Y. Brain iron metabolism disorder involved in the pathogenesis and treatment strategy of Alzheimer's disease[A]. Compilation of the 24th National Congress of the Chinese Physiological Society and the Conference of Physiology[C], 2014.
[91] Wang C Y, Wang T, Zheng W, et al. Zinc overload enhances APP cleavage and Abeta deposition in the Alzheimer mouse brain[J]. PLoS One, 2010, 5: e15349.
[92] Lu T, Nguyen B, Zhang X, et al. Architecture of a K+ Channel Inner Pore Revealed by Stoichiometric Covalent Modification[J]. Neuron, 1999, 22(3): 571-580.
[93] Yang J, Elllnor P T, Sather W A, et al. Molecular determinants of Ca2+ selectivity and ion permeation in L-type Ca2+ channels[J]. Nature (London), 1993, 366(6451):158-161.
[94] Consiglio J F, Andalib P, Korn S J. Influence of Pore Residues on Permeation Properties in the Kv2.1 Potassium Channel. Evidence for a Selective Functional Interaction of K+ with the Outer Vestibule[J]. Journal of General Physiology, 2003, 121(2): 111-124.
[95] Heinemann S H, Terlau H, Stühmer W, et al. Calcium channel characteristics conferred on the sodium channel by single mutations[J]. Nature (London), 1992, 356(6368): 441-443.
[96] Palmer A M. The role of the blood-CNS barrier in CNS disorders and their treatment [J]. Neurobiology of Disease, 2010, 37(1): 3-12.
[97] Brightman M W, Reese T S. Junctions between intimately apposed cell membranes in the vertebrate brain[J]. J Cell Biol. 1969, 40(3): 648-677.
[98] Wolburg H, Noell S, Mack A, et al. Brain endothelial cells and the glio-vascular complex[J]. Cell and Tissue Research, 2009, 335(1): 75-96.
[99] Mullins L J. Ion selectivity of carriers and channels[J]. Biophysical Journal, 1975, 15(9): 921-931.
[100] Nimigean C M, Chappie J S, Miller C. Electrostatic Tuning of Ion Conductance in Potassium Channels[J]. Biochemistry, 2003, 42(31): 9263-9268.
[101] Hille B. Potassium Channels in Myelinated Nerve: Selective permeability to small cations[J]. Journal of General Physiology, 1973, 61(6): 669.
[102] Bezanilla F, Armstrong C M. Negative Conductance Caused by Entry of Sodium and Cesium Ions into the Potassium Channels of Squid Axons[J]. Journal of General Physiology, 1972, 60(5): 588-608.
[103] Huxley A F. Hodgkin and the action potential[J]. J Physiol, 2002, 538:2.
[104] Roux B T. Ion conduction and selectivity in K(+) channels[J]. Annual Review of Biophysics & Biomolecular Structure, 2005, 34(34): 153-171.
[105] Han Y R. Molecular Cell Biology (The Fourth edition) [M] . Beijing: Science Press, 2012.
[106] Kuffler S W, Nicholls J G. The physiology of neuroglial cells[J]. Ergeb Physiol, 1966, 57(1): 1-90.
[107] Kofuji P, Newman E A. Potassium buffering in the central nervous system[J]. Neuroscience, 2004, 129(4): 1043-1054.
[108] Kofuji P, Ceelen P, Zahs K R, et al. Genetic Inactivation of an Inwardly Rectifying Potassium Channel (Kir4.1 Subunit) in Mice: Phenotypic Impact in Retina[J]. The Journal of Neuroscience, 2000, 20(15): 5733-5740.
[109] Madsen E, Gitlin J D. Copper and iron disorders of the brain[J]. Annu Rev Neurosci, 2007, 30: 317-337.
[110] Wang C, Liu P, Wang X L, et al. Metal Ions and Alzheimer's Disease[J]. Sichuan Medical Journal, 2008, 29(4): 467-469.
[111] Phillips R, Kondev J, Theriot J. Physical Biology of the Cell[M]. Beijing: Science Press, 2012.
[112] Doty R L, Olfaction in Parkinson's disease and related disorders[J]. Neurobiol Dis, 2012, 46(3): 527-552.
[113] Ulla M, Bonny J M, Ouchchane L, et al. Is R2 a new MRI biomarker for the progression of Parkinson's disease? A longitudinal follow-up[J]. PLoS One, 2013, 8(3): e57904.
[114] Xu J, Gong D D, Man C F, et al. Parkinson's disease and risk of mortalitv: meta- analvsis and svstematic review[J]. Acta Neurol Scand, 2014, 129(2): 71-79.
[115] Luckey T D, Venugopal B. Metal Toxicity in Mammals[J]. Chemical Toxicity of Metals and Metalloids, 1978, 2: 32-36.
[116] Nichols C G, Lopatin A N. Inward rectifier potassium channels[J]. Annual Review of Physiology, 1997, 59(1): 171-191.
[117] Lu Z. Mechanism of rectification in inward-rectifier K+ channels[J]. Annu Rev Physiol. 2004, 66(1): 103-129.
[118] Armstrong C M. Interaction of Tetraethylammonium Ion Derivatives with the Potassium Channels of Giant Axons[J]. Journal of General Physiology, 1971, 58(4): 413-437.
[119] Armstrong C M. Time Course of TEA+-Induced Anomalous Rectification in Squid Giant Axons[J]. Journal of General Physiology, 1966, 50(2): 491-503.
[120] Lu T, Ting A Y, Mainland J, et al. Probing ion permeation and gating in a K+ channel with backbone mutations in the selectivity filter[J]. Nature Neuroscience, 2001, 4(3): 239 -246.
[121] Bao H, Hakeem A, Henteleff M, et al. Voltage-insensitive Gating after Charge- neutralizing Mutations in the S4 Segment of Shaker Channels[J]. The Journal of General Physiology, 1999, 113(1): 139-151.
[122] Bruening-Wright A, Schumacher M A, Adelman J P, et al. Localization of the activation gate for small conductance Ca2+-activated K+ channels[J]. The Journal of Neuroscience, 2002, 22(15): 6499-6506.
[123] Korn S J, Trapani J G. Potassium channels[J]. IEEE Trans Nanobiosci, 2005, 4(1): 21- 33.
[124] Flynn G E, Johnson J P Jr, Zagotta W N. Cyclic nucleotide-gated channels: shedding light on the opening of a channel pore[J]. Nature Rev Neurosci, 2001, 2: 643-652.
[125] Liu Y, Joho R H. A side chain in S6 influences both open-state stability and ion permeation in a voltage-gated K+channel[J]. Pfluegers Archiv European Journal of Physiology, 1998, 435(5): 654-661.
[126] Heginbotham L, Lu Z, Abramson T, et al. Mutations in the K+ channel signature sequence[J]. Biophysical Journal, 1994, 66(4): 1061-1067.
[127] Schrempf H, Schmidt O, Kümmerlen R, et al. A prokaryotic potassium ion channel with two predicted transmembrane segments from Streptomyces lividans[J]. The EMBO journal, 1995, 14(21): 5170-5178.
[128] Heginbotham L, Odessey E, Miller C. Tetrameric stoichiometry of a prokaryotic K+ channel[J]. Biochemistry, 1997, 36(33): 10335.
[129] MacKinnon R. Determination of the subunit stoichiometry of a voltage-activated potassium channel[J]. Nature, 1991, 350(6315): 232.
[130] Ketchum K A, Joiner W J, Sellers A J, et al. A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem[J]. Nature, 1995, 376(6542): 690-695.
[131] MacKinnon R. Structural Conservation in Prokaryotic and Eukaryotic Potassium Channels[J]. Science, 1998, 280(5360): 106-109.
[132] Mackinnon R, Miller C. Mutant potassium channels with altered binding of charybdotoxin, a pore-blocking peptide inhibitor[J]. Science, 1989, 245(4924): 1382-1385.
[133] Mackinnon R, Heginbotham L, Abramson T. Mapping the receptor site for charybdotoxin, a pore-blocking potassium channel inhibitor[J]. Neuron, 1990, 5(6): 767-771.
[134] Hidalgo P, Mackinnon R. Revealing the architecture of a K+ channel pore through mutant cycles with a peptide inhibitor[J]. Science, 1995, 268(5208): 307-310.
[135] Abbracchio M P, Burnstock G, Verkhratsky A, et al. Purinergic signalling in the nervous system: an overview[J]. Trends in Neurosciences, 2009, 32(1): 19-29.
[136] Jarvis M F, Khakh B S. ATP-gated P2X cation-channesl[J]. Neuropharmacol, 2009, 56:208-215.
[137] Skou J C. The influence of some cations on an adenosine triphosphatase from pheripheral nerves[J]. Biochim Biophys Acta, 1957, 23: 394-401.
[138] Caldwell P C, Hodgkin A L, Keynes R D, et al. The effect of injecting
[139] Hodgkin A L, Keynes R D. Active transport of cations in giant axons from Sepia and Loligo[J]. J Physiol, 1955, 128(1): 28-60.
[140] Rizzuto R, Pozzan T. Microdomains of Intracellular Ca2+: Molecular Determinants and Functional Consequences[J]. Physiol Rev, 2006, 86(1): 369-408.
[141] Carafoli E, Brini M. Calcium pumps: structural basis for and mechanism of calcium transmembrane transport[J]. Curr Opin Chem Biol, 2000, 4(2): 152-161.
[142] MacLennan D H, Abu-Abed M, Kang C. Structure-function relationships in Ca(2+) cycling proteins[J]. J Mol Cell Cardiol, 2002, 34(8): 897-918.
[143] Baker P F, Blaustein M P, Keynes R D, et al. The ouabain-sensitive fluxes of sodium and potassium in squid giant axons.[J]. J Physiol, 1969, 200(2): 459-496.
[144] Skou J C. The Na,K-pump[J]. Methods in Enzymology, 1988, 156:1-25.
[145] Thomas R C. Membrane current and intracellular sodium changes in a snail neuron during extrusion of injected sodium[J]. J Physiol, 1969, 201: 495-514.
[146] Thomas R C. Intracellular sodium activity and the sodium pump in snail neurons[J]. J Physiol, 1972, 220: 55-71.
[147] Jorgensen P L, Hakansson K O, Karlish S J. Structure and mechanism of Na, K-ATPase: functional sites and their interactions[J]. Annual Review of Physiology, 2003, 65: 817-849.
[148] Zhao J, Zhang Y M, Zheng N Z. Research progress on mechanism of comorbidity of epilepsy and Alzheimer disease[J]. China Medical Herald, 2017, 14(21): 53-56.
[149] Nelson P T, Schmitt F A, Lin Y, et al. Hippoeampal sclerosis in advanced age: clinical and pathological features[J]. Brain, 2011, 134(5): 1506-1518.
[150] Palop J J, Chin J, Roberson E D, et al. Aberrant excitatory neuronal activity and compensatory remodelingof inhibitory hippocampal circuits in mouse models of Alzheimer disease[J]. Neuron, 2007, 55(5): 697-711.
[151] Scarmaes N, Honig L S, Choi H. Seizure in Alzheimer disease: whowhen, and how common [J]. Arch Network, 2009, 66(8): 435-440.
[152] Amatiniek J C, Hauser W A, DelCastillo-Castaneda C, et al. Incidene and predictors of seizures in patients with Alzheimer disease[J]. Epileosia, 2006, 47(5): 867-872.
[153] Scharfman H E. Alzheimer's disease and epilepsy: insight from animal models[J].Future Neurol, 2012, 7(2): 177-192.
[154] Hall A M, Throesch B T, Buckingham S C, et al. Tau-dependent Kv4.2 depiltion and dendeitic hyperexcitability in a mouse model of Alzheimer disease[J]. J Neurosci, 2015, 35 (15): 6221-6230.
[155] Glenner G G, Wong C W. Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein[J]. Biochem Biophys Res Commun, 1984, 120: 885-890.
[156] Zhao J, O'Connor T, Vassar R. The contribution of activated astrocytes to Aβ production: implications for Alzheimer's disease pathogenesis[J]. J Neuroinflamm, 2011, 8:150.
[157] Citron M, Diehl T S, Gordon G, et al. Evidence that the 42- and 40-amino acid forms of amyloid β protein are generated from theβ-amyloid precursor protein by different protease activities[J]. Proc Natl Acad Sci USA, 1996, 93: 13170-13175.
[158] Zhang Y W, Thompson R, Zhang H, et al. APP processing in Alzheimer's disease[J]. Mol Brain, 2011, 4:3.
[159] Thal D R. The role of astrocytes in amyloid β-protein toxicity and clearance[J]. Exp Neurol, 2012, 236:1-5.
[160] Nicoll J A, Weller R O. A new role for astrocytes: β-amyloid homeostasis and degradation[J]. Trends Mol Med, 2003,9:281-282.
[161] Fu W, Shi D, Westaway D, et al. Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity[J]. J Biol Chem, 2015, 290:12504-12513.
[162] Nagele R G, D'Andrea M R, Lee H, et al. Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer's disease brains[J]. Brain Res, 2003, 971:197-209.
[163] Wyss-Coray T, Loike J D, Brionne T C, et al. Adult mouse astrocytes degrade amyloid- β in vitro and in situ[J]. Nat Med, 2003, 9: 453-457.
[164] Batarseh Y S, Duong Q V, Mousa Y M, et al. Amyloid-β and astrocytes interplay in amyloid-β related disorders[J]. Int J Mol Sci, 2016, 17: 338.
[165] Kurnellas M P, Adams C M, Sobel R A, et al. Amyloid Fibrils Composed of Hexameric Peptides Attenuate Neuroinflammation[J]. Science translational medicine, 2013, 5(179):179ra42.
[166] Chemy R A, Legg J T, McLean C A, et al. Aqueous Dissolution of Alzheimer's Disease A βAmyloid Deposits by Biometal Depletion[J]. J Biol Chem, 1999, 274:23223-23228.
[167] Bush A I . Metal complexing agents as therapies for Alzheimer's disease[J]. Neurobiology of Aging, 2002, 23(6):1031-1038.
[168] Bush A I, Tanzi R E. The galvanization of β-amyloid in Alzheimer's disease[J]. Proc Natl Acad Sci U S A, 2002, 99 (11): 7317-7319.
[169] Lannfelt L, Blennow K, Zetterberg H, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomized, placebo-controlled trial[J]. Lancet Neurol, 2008, 7(9): 779-786.
[170] Storr T, Merkel M, Song-Zhao G X, et al. Synthesis, characterization, and metal coordinating ability of multifunctional carbohydrate-containing compounds for Alzheimer's therapy[J]. J Am Chem Soc, 2007, 129(23): 7453-7463.
[171] Hamblcy T W. Chemistry: Metal-based therapeutics[J]. Science, 2007, 318(5855): 1392- 1393.
[172] Cherny R A, Atwood C S, Xilinas M E, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibitsβ-amyloid accumulation in Alzheimer's disease transgenic mice[J]. Neuron, 2001, 30(3): 665-676.
[173] Tang Q, Zou W, Sun Z D, et al. Clinical study on transcranial magnetoelectric encephalopathy treatment instrument for Alzheimer's disease[J]. Highlights of Sciencepaper Online, 2017, 10(11): 1-7.
[174] Zou W, Tang Q, Sun Z D, et al. Clinical study on Transcranial magnetoelectric encephalopathy treatment instrument treatmenting vascular dementia[EB/OL]. Beijng: ChinaXiv [2017-01-19] .DOI: 10.12074/201701.00088.
[175] Tang Q, Zou W, Sun Z D, et al. Clinical study on Transcranial magnetoelectric encephalopathy treatment instrument treatmenting parkinson's disease[EB/OL]. Beijng: Sciencepaper Online[2017-02-08]. http://www.paper.edu.cn/releasepaper/content/201702-38.
[176] Xing X L, Tang Q. Clinical research on influences of transcranial magnetoelectric stimulation on Parkinson's disease[A]. The assembly of conference papers of the 11th national rehabilitation academic conference of Exercise Therapy Branch of Chinese Association of Rehabilitation Medicine[C], 2011.
[177] Zhang W, Wang X Y, Guo H Q, et al. Therapeutic effect of repetitive transcranial magnetic therapy on KA induced epileptic rats[J]. Chinese Journal of Neuromedicine, 2018, 17(7): 673-677.
[178] Xia X Y, Yang Y, Bai Y, et al. Application of transcranial magnetic stimulation combined with electroence-phalography in consciousness discrimination of patients with disturbance of consciousness[J]. Chin J Neuromed, 2016, 15(4): 425-428.
[179] Kimiskidis VK, Valentin A, Kälviäinen R. Transcranial magnetic stimulation for the diagnosis and treatment of epilepsy[J]. Curr Opin Neurol, 2014, 27(2): 236-241.
[180] Ruffolo G, Di BC, Cifelli P, et al. A novel action of lacosamide on GABAA currents sets the ground for a synergic interaction with levetiracetam in treatment of epilepsy[J]. Neurobiol Dis, 2018, 115: 59-68.
[181] Jiang Z, Guo M, Shi C, et al. Protection against cognitive impairment and modification of epileptogenesis with curcumin in a post-status epilepticus model of temporal lobe epilepsy [J].Neuroscience, 2015, 310: 362-371.
[182] Liu A, Bryant A, Jefferson A, et al. Exploring the efficacy of a 5-day course of transcranial direct current stimulation (TDCS) on depression and memory function in patients with well-controlled temporal lobe epilepsy[J]. Epilepsy Behav, 2016, 55: 11-20.
[183] Tang A, Thickbroom G, Rodger J. Repetitive Transcranial Magnetic Stimulation of the Brain:Mechanisms from Animal and xperimental Models[J]. Neuroscientist, 2015, 23(1): 1-13.
[184] Bear M F, Connors B W, Paradiso M A. Synaptic Transmission. In: Neuroscience: exploring the brain[M]. Philadelphia: Lippincott Williams, wilkins inc, 2001.
[185] Burgoyne R D, Morgan A. Secretory granule exocytosis[J]. Physiological Reviews, 2003, 83(2): 581-632.
[186] Schneggenburger R, Neher E. Presynaptic calcium and control of vesicle fusion[J]. Current Opinion in Neurobiology, 2005,15(3): 266-274.
[187] Rizo J, Chen X, Arac D. Unraveling the mechanisms of synaptotagmin and SNARE function in neurotransmitter release[J]. Trends Cell Biol, 2006, 16(7): 339-350.

作者简介：孙作东（1966），男，研究员、博士后合作导师，主要研究方向：脑科学基础理论研究与重大脑病康复治疗设备的研发. E-mail: sunzuodong@pai314.com