Glutamate system, amyloid β peptides and tau protein: Functional interrelationships and relevance to Alzheimer disease pathology

Journal of Psychiatry and Neuroscience

Volumn 38, Issue 1, 2013, Pages 6-23

  Revett, Timothy J ^a   Baker, Glen B ^a   Jhamandas, Jack ^a   Kar, Satyabrata ^a  

^a UNIVERSITY OF ALBERTA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 5 PHOSPHONOVALERIC ACID; 4 BENZYL ALPHA (4 HYDROXYPHENYL) BETA METHYL 1 PIPERIDINEPROPANOL; AMANTADINE; AMPA RECEPTOR; AMYLOID BETA PROTEIN; CASPASE 3; DEXTROMETHORPHAN; DIZOCILPINE; EXCITATORY AMINO ACID TRANSPORTER 1; EXCITATORY AMINO ACID TRANSPORTER 2; GLUTAMIC ACID; IFENPRODIL; IONOTROPIC RECEPTOR; MEMANTINE; METABOTROPIC RECEPTOR; MITOGEN ACTIVATED PROTEIN KINASE 3; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; PHENCYCLIDINE; PROTEIN KINASE C; PROTEIN TYROSINE PHOSPHATASE; TAU PROTEIN; VESICULAR GLUTAMATE TRANSPORTER 1; VESICULAR GLUTAMATE TRANSPORTER 2; AMINO ACID RECEPTOR BLOCKING AGENT;

ALZHEIMER DISEASE; AMNESIA; ASTROCYTE; ATAXIA; CELL STRUCTURE; CELL SURVIVAL; DEGENERATIVE DISEASE; DEMENTIA; DENDRITIC SPINE; DRUG EFFICACY; HALLUCINATION; HIPPOCAMPAL CA1 REGION; HUMAN; ISCHEMIA; LONG TERM DEPRESSION; LONG TERM POTENTIATION; MOLECULAR PATHOLOGY; NERVE CELL PLASTICITY; NERVE DEGENERATION; NERVE FUNCTION; NONHUMAN; POSTSYNAPTIC DENSITY; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN TRANSPORT; REVIEW; SIGNAL TRANSDUCTION; TRAUMATIC BRAIN INJURY; ANIMAL; BRAIN; DRUG EFFECTS; METABOLISM; NEUROFIBRILLARY TANGLE; PATHOLOGY; PATHOPHYSIOLOGY; PHOSPHORYLATION; PHYSIOLOGY; SYNAPTIC MEMBRANE;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; ANIMALS; BRAIN; EXCITATORY AMINO ACID ANTAGONISTS; GLUTAMIC ACID; HUMANS; MEMANTINE; NEUROFIBRILLARY TANGLES; PHOSPHORYLATION; SYNAPTIC MEMBRANES; TAU PROTEINS;

EID: 84871601359     PISSN: 11804882     EISSN: 14882434     Source Type: Journal    
DOI: 10.1503/jpn.110190     Document Type: Article

References (219)

1. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-7.
2. Guerreiro RJ, Gustafson DR, Hardy J. The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE. Neurobiol Aging. In press.
3. St George-Hyslop PH, Petit A. Molecular biology and genetics of Alzheimer's disease. C R Biol 2005;328:119-30.
4. Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 2009;41:1088-93.
5. Lambert JC, Heath S, Even G, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 2009;41:1094-9.
6. Seshadri S, Fitzpatrick AL, Ikram MA, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 2010; 303: 1832-40.
7. Rogaeva E, Meng Y, Lee JH, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007;39:168-77.
8. Hollingworth P, Harold D, Jones L, et al. Alzheimer's disease gen-etics: current knowledge and future challenges. Int J Geriatr Psychiatry 2011;26:793-802.
9. Lambert JC, Amouyel P. Genetics of Alzheimer's disease: New evidences for an old hypothesis? Curr Opin Genet Dev 2011;21:295-301.
10. Guskiewicz KM, Marshall SW, Bailes J, et al. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery 2005;57:719-26.
11. de la Torre JC. How do heart disease and stroke become risk factors for Alzheimer's disease? Neurol Res 2006;28:637-44.
12. Hölscher C. Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. Biochem Soc Trans 2011;39:891-7.
13. Chen J-H, Lin K-P, Chen Y-C. Risk factors for dementia. J Formos Med Assoc 2009;108:754-64.
14. Butterfield DA, Pocernich CB. The glutamatergic system and Alzheimer's disease: therapeutic implications. CNS Drugs 2003;17: 641-52.
15. Selkoe DJ, Schenk D. Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 2003; 43:545-84.
16. Combs B, Voss K, Gamblin TC. Pseudohyperphosphorylation has differential effects on polymerization and function of tau isoforms. Biochemistry 2011;50:9446-56.
17. Mi K, Johnson GV. The role of tau phosphorylation in the pathogenesis of Alzheimer's disease. Curr Alzheimer Res 2006;3:449-63.
18. Wang JZ, Grundke-Iqbal I, Iqbal K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 2007;25:59-68.
19. Braak H, Braak E. Evolution of neuronal changes in the course of Alzheimer's disease. J Neural Transm Suppl 1998;53:127-40.
20. Chow VW, Mattson MP, Wong PC, et al. An overview of APP processing enzymes and products. Neuromolecular Med 2010;12:1-12.
21. LeBlanc AC, Chen HY, Autilio-Gambetti L, et al. Differential APP gene expression in rat cerebral cortex, meninges, and primary astroglial, microglial and neuronal cultures. FEBS Lett 1991;292:171-8.
22. Mills J, Reiner PD. Regulation of amyloid precursor protein cleavage. J Neurochem 1999;72:443-60.
23. Murphy MP, Levine H. Alzheimer's disease and the amyloid-beta peptide. J Alzheimers Dis 2010;19:311-23.
24. Näslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000;283:1571-7.
25. Blurton-Jones M, Laferla FM. Pathways by which Aβ facilitates tau pathology. Curr Alzheimer Res 2006;3:437-48.
26. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature 2004;430:631-9.
27. Alberdi E, Sanchez-Gomez MV, Cavaliere F, et al. Amyloid β oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 2010;47: 264-72.
28. Supnet C, Bezprozvanny I. The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium 2010;47:183-9.
29. Hynd MR, Scott HL, Dodd PR. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. Neurochem Int 2004; 45: 583-95.
30. Dasilva KA, Shaw JE, McLaurin J. Amyloid-β fibrillogenesis: structural insight and therapeutic intervention. Exp Neurol 2010;223: 311-21.
31. Morgan D. Immunotherapy for Alzheimer's disease. J Intern Med 2011;269:54-63.
32. Pahnke J, Walker LC, Scheffler K, et al. Alzheimer's disease and blood-brain barrier function-Why have anti-β-amyloid therapies failed to prevent dementia progression? Neurosci Biobehav Rev 2009; 33:1099-108.
33. Samadi H, Sultzer D. Solanezumab for Alzheimer's disease. Expert Opin Biol Ther 2011;11:787-98.
34. DeKosky ST, Scheff SW, Styren SD. Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 1996;5:417-21.
35. Francis PT. Glutamatergic systems in Alzheimer's disease. Int J Geriatr Psychiatry 2003;18:S15-21.
36. Bell KF, Bennett DA, Cuello AC. Paradoxical upregulation of gluta matergic presynaptic boutons during mild cognitive impairment. J Neurosci 2007;27:10810-7.
37. Kar S, Slowikowski SP, Westaway D, et al. Interactions between β-amyloid and central cholinergic neurons: implications for Alzheimer's disease. J Psychiatry Neurosci 2004;29:427-41.
38. Morris JC. Challenging assumptions about Alzheimer's disease: mild cognitive impairment and the cholinergic hypothesis. Ann Neurol 2002;51:143-4.
39. Bell KFS, Cuello AC. Altered synaptic function in Alzheimer's disease. Eur J Pharmacol 2006;545:11-21.
40. Dijk SN, Francis PT, Stratmann GC, et al. Cholinomimetics increase glutamate outflow via an action on the corticostriatal pathway: implications for Alzheimer's disease. J Neurochem 1995;65: 2165-9.
41. Tsang SWY, Pomakian J, Marshall GA, et al. Disrupted muscarinic M1 receptor signalling correlates with loss of protein kinase C activity and glutamatergic deficit in Alzheimer's disease. Neurobiol Aging 2007;28:1381-7.
42. Kowall NW, Beal MF. Glutamate-, glutaminase-, and taurineimmunoreactive neurons develop neurofibrillary tangles in Alzheimer's disease. Ann Neurol 1991;29:162-7.
43. Bussière T, Giannakopoulos P, Bouras C, et al. Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer's disease: stereologic analysis of prefrontal cortex area 9. J Comp Neurol 2003;463:281-302.
44. Fremeau RT Jr, Troyer MD, Pahner I, et al. The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron 2001;31:247-60.
45. Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl) 2005;179:4-29.
46. Ozawa S, Kamiya H, Tsuzuki K. Glutamate receptors in the mammalian central nervous system. Prog Neurobiol 1998;54:581-618.
47. Danbolt NC. Glutamate uptake. Prog Neurobiol 2001;65:1-105.
48. Ferraguti F, Shigemoto R. Metabotropic glutamate receptors. Cell Tissue Res 2006;326:483-504.
49. Gerber U, Gee CE, Benquet P. Metabotropic glutamate receptors: intracellular signalling pathways. Curr Opin Pharmacol 2007;7:56-61.
50. Schools GP, Kimelberg HK. mGluR3 and mGluR5 are the predom-inant metabotropic glutatmate receptor mRNAs expressed in hippo-campal astrocytes acutely isolated from young rats. J Neurosci Res 1999; 58:533-43.
51. Vogt KE, Nicoll RA. Glutamate and γ-aminobutyric acid mediate a heterosynaptic depression at mossy fiber synapses in the hippo-campus. Proc Natl Acad Sci U S A 1999;96:1118-22.
52. Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 2000;32:1-14.
53. Storck T, Schulte S, Hofmann K, et al. Structure, expression, and functional analysis of a Na+-dependent glutamate/aspartate transporter from rat brain. Proc Natl Acad Sci U S A 1992;89:10955-9.
54. Pines G, Danbolt NC, Bjoras M, et al. Cloning and expression of a rat brain L-glutamate transporter. Nature 1992;360:464-7.
55. Shashidharan P, Huntley GW, Meyer T, et al. Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain. Brain Res 1994;662:245-50.
56. Kashani A, Lepicard E, Poirel O, et al. Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease. Neurobiol Aging 2008;29:1619-30.
57. Kirvell SL, Esiri M, Francis PT. Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer's disease. J Neurochem 2006;98:939-50.
58. Sokolow S, Luu SH, Nandy K, et al. Preferential accumulation of amyloid β in presynaptic glutamatergic terminals (VGLUT1 and VGLUT2) in Alzheimer's disease cortex. Neurobiol Dis 2012;45:381-7.
59. Jacob CP, Koutsilieri E, Bartl J, et al. Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer's disease. J Alzheimers Dis 2007;11:97-116.
60. Scott HA, Gebhardt FM, Mitrovic AD, et al. Glutamate transporter variants reduce glutamate uptake in Alzheimer's disease. Neurobiol Aging 2011;32:553. e1-11.
61. Robinson SR. Changes in the cellular distribution of glutamine synthetase in Alzheimer's disease. J Neurosci Res 2001;66:972-80.
62. Hynd MR, Scott HL, Dodd PR. Selective loss of NMDA receptor NR1 subunit isoforms in Alzheimer's disease. J Neurochem 2004;89: 240-7.
63. Hynd MR, Scott HL, Dodd PR. Differential expression of N-methyl Daspartate receptor NR2 isoforms in Alzheimer's disease. J Neuro chem 2004;90:913-9.
64. Williams C, Mehrian Shai R, Wu Y, et al. Transcriptome analysis of synaptoneurosomes identifies neuroplasticity genes overexpressed in incipient Alzheimer's disease. PLoS ONE 2009;4:e4936.
65. Pellegrini-Giampietro DE, Bennett MV, Zukin RS. AMPA/kainate receptor gene expression in normal and Alzheimer's disease hippocampus. Neuroscience 1994;61:41-9.
66. Yasuda RP, Ikonomovic MD, Sheffield R, et al. Reduction of AMPA-selective glutamate receptor subunits in the entorhinal cortex of patients with Alzheimer's disease pathology: a biochemical study. Brain Res 1995;678:161-7.
67. Dewar D, Chalmers DT, Graham DI, et al. Glutamate metabotropic and AMPA binding sites are reduced in Alzheimer's disease: an autoradiographic study of the hippocampus. Brain Res 1991;553:58-64.
68. Aronica E, Dickson DW, Kress Y, et al. Non-plaque dystrophic dendrites in Alzheimer hippocampus: a new pathological structure revealed by glutamate receptor immunocytochemistry. Neuroscience 1998;82:979-91.
69. Albasanz JL, Dalfo E, Ferrer I, et al. Impaired metabotropic glutamate receptor/phospholipase C signaling pathway in the cerebral cortex in Alzheimer's disease and dementia with Lewy bodies correlates with stage of Alzheimer's-disease-related changes. Neurobiol Dis 2005;20: 685-93.
70. Lee HG, Ogawa O, Zhu X, et al. Aberrant expression of meta-botropic glutamate receptor 2 in the vulnerable neurons of Alz-heimer's disease. Acta Neuropathol 2004;107:365-71.
71. Masliah E, Alford M, DeTeresa R, et al. Deficient glutamate transport is associated with neurodegeneration in Alzheimer's disease. Ann Neurol 1996;40:759-66.
72. Li S, Mallory M, Alford M, et al. Glutamate transporter alterations in Alzheimer's disease are possibly associated with abnormal APP expression. J Neuropathol Exp Neurol 1997;56:901-11.
73. Matos M, Augusto E, Oliveira CR, et al. Amyloid-β peptide decreases glutamate uptake in cultured astrocytes: involvement of oxidative stress and mitogen-activated protein kinase cascades. Neuroscience 2008;156:898-910.
74. Parihar MS, Brewer GJ. Mitoenergetic failure in Alzheimer disease. Am J Physiol Cell Physiol 2007;292:C8-23.
75. Greenamyre JT, Maragos WF, Albin RL, et al. Glutamate transmission and toxicity in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 1988;12:421-30.
76. Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxi-city and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin 2009;30:379-87.
77. Vosler PS, Brennan CS, Chen J. Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration. Mol Neurobiol 2008;38:78-100.
78. Ułas J, Weihmuller FB, Brunner LC, et al. Selective increase of NMDA-sensitive glutamate binding in the striatum of Parkinson's disease, Alzheimer's disease, and mixed Parkinson's disease / Alzheimer's disease patients: an autoradiographic study. J Neurosci 1994;14:6317-24.
79. Ikonomovic MD, Mizukami K, Warde D, et al. Distribution of glutamate receptor subunit NMDAR1 in the hippocampus of normal elderly and patients with Alzheimer's disease. Exp Neurol 1999; 160: 194-204.
80. Panegyres PK, Zafiris-Toufexis K, Kakulas BA. The mRNA of the NR1 subtype of glutamate receptor in Alzheimer's disease. J Neural Transm 2002;109:77-89.
81. Sze C, Bi H, Kleinschmidt-DeMasters BK, et al. N-methyl-D-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer's disease. J Neurol Sci 2001;182: 151-9.
82. Allinson TM, Parkin ET, Turner AJ, et al. ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res 2003; 74:342-52.
83. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 2001;81:741-66.
84. Clippingdale AB, Wade JD, Barrow CJ. The amyloid-β peptide and its role in Alzheimer's disease. J Pept Sci 2001;7:227-49.
85. Plant LD, Boyle JP, Smith IF, et al. The production of amyloid peptide is a critical requirement for the viability of central neur ons. J Neurosci 2003;23:5531-5.
86. Roberson MR, Harrell LE. Cholinergic activity and amyloid precursor protein metabolism. Brain Res Brain Res Rev 1997;25:50-69.
87. Hoey SE, Williams RJ, Perkinton MS. Synaptic NMDA receptor activation stimulates α-secretase amyloid precursor protein processing and inhibits amyloid-β production. J Neurosci 2009;29:4442-60.
88. Lee RK, Jimenez J, Cox AJ, et al. Metabotropic glutamate receptors regulate APP processing in hippocampal neurons and cortical astrocytes derived from fetal rats. Ann N Y Acad Sci 1996;777:338-43.
89. Marcello E, Gardoni F, Mauceri D, et al. Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes activity. J Neurosci 2007;27:1682-91.
90. da Cruz e Silva OA, Rebelo S, Vieira SI, et al. Enhanced generation of Alzheimer's amyloid-β following chronic exposure to phorbol ester correlates with differential effects on α and ε isozymes protein kinase C. J Neurochem 2009;108:319-30.
91. Bordji K, Becerril-Ortega J, Nicole O, et al. Activation of extrasyn aptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-β production. J Neurosci 2010;30:15927-42.
92. Lesné S, Ali C, Gabriel C, et al. NMDA receptor activation inhibits secretase and promotes neuronal amyloid-β production. J Neuro 2005;25:9367-77.
93. Cirrito JR, Kang JE, Lee J, et al. Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo. Neuron 2008;58:42-51.
94. Kim SH, Fraser PE, Westaway D, et al. Group II metabotropic glutamate receptor stimulation triggers production and release Alzheimer's amyloidß42 from isolated intact nerve terminals. J Neurosci 2010;30:3870-5.
95. Tang BL. Neuronal protein trafficking associated with Alzheimer disease: from APP and BACE1 to glutamate receptors. Cell Adh Migr 2009;3:118-28.
96. Kullmann DM, Lamsa KP. Long-term synaptic plasticity in hippo campal interneurons. Nat Rev Neurosci 2007;8:687-99.
97. Morris RG. Long-term potentiation and memory. Philos Trans Soc Lond B Biol Sci 2003;358:643-7.
98. Shankar GM, Li S, Mehta TH, et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008;14:837-42.
99. Cullen WK, Suh YH, Anwyl R, et al. Block of LTP in rat hippocampus in vivo by β-amyloid precursor protein fragments. Neuroreport 1997; 8:3213-7.
100. Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 2003;39:409-21.
101. Townsend M, Qu Y, Gray A, et al. Oral treatment with a γ-secretase inhibitor improves long-term potentiation in a mouse model Alzheimer's disease. J Pharmacol Exp Ther 2010;333:110-9.
102. Klyubin I, Betts V, Welzel AT, et al. Amyloid β protein dimer containing human CSF disrupts synaptic plasticity: prevention systemic passive immunization. J Neurosci 2008;28:4231-7.
103. Shankar GM, Bloodgood BL, Townsend M, et al. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptordependent signaling pathway. J Neurosci 2007;27:2866-75.
104. Li S, Jin M, Koeglsperger T, et al. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci 2011;31:6627-38.
105. Selkoe DJ. Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior. Behav Brain Res 2008;192:106-13.
106. Wei W, Nguyen LN, Kessels HW, et al. Amyloid β from axons and dendrites reduces local spine number and plasticity. Nat Neurosci 2010; 13:190-6.
107. Knafo S, Alonso-Nanclares L, Gonzalez-Soriano J, et al. Widespread changes in dendritic spines in a model of Alzheimer's disease. Cereb Cortex 2009;19:586-92.
108. Hsieh H, Boehm J, Sato C, et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 2006; 52: 831-43.
109. Kim JH, Anwyl R, Suh YH, et al. Use-dependent effects of amyloidogenic fragments of β-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo. J Neurosci 2001;21:1327-33.
110. Li S, Hong S, Shepardson NE, et al. Soluble oligomers of amyloidß protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 2009;62:788-801.
111. Masliah E, Alford M, Mallory M, et al. Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice. Exp Neurol 2000;163:381-7.
112. Scott HL, Pow DV, Tannenberg AE, et al. Aberrant expression of the glutamate transporter excitatory amino acid transporter 1 (EAAT1) in Alzheimer's disease. J Neurosci 2002;22:RC206.
113. Zhao WQ, Santini F, Breese R, et al. Inhibition of calcineurin-mediated endocytosis and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloidß oligomer-induced synaptic disruption. J Biol Chem2010;285:7619-32.
114. Klyubin I, Wang Q, Reed MN, et al. Protection against Aβ-mediated rapid disruption of synaptic plasticity and memory by memantine. Neurobiol Aging 2011;32:614-23.
115. Lacor PN, Buniel MC, Chang L, et al. Synaptic targeting by Alzheimer's-related amyloid β oligomers. J Neurosci 2004;24:10191-200.
116. Fernández-Tomé P, Brera B, Arevalo MA, et al. β-amyloid25-35 inhibits glutamate uptake in cultured neurons and astrocytes: modulation of uptake as a survival mechanism. Neurobiol Dis 2004;15: 580-9.
117. Chin JH, Ma L, MacTavish D, et al. Amyloid β protein modulates glutamate-mediated neurotransmission in the rat basal forebrain: involvement of presynaptic neuronal nicotinic acetylcholine and metabotropic glutamate receptors. J Neurosci 2007;27:9262-9.
118. Kabogo D, Rauw G, Amritraj A, et al. β-amyloid-related peptides potentiate K+-evoked glutamate release from adult rat hippocampal slices. Neurobiol Aging 2010;31:1164-72.
119. Opazo P, Choquet D. A three-step model for the synaptic recruitment of AMPA receptors. Mol Cell Neurosci 2011;46:1-8.
120. Gong Y, Lippa CF. Review: disruption of the postsynaptic density in Alzheimer's disease and other neurodegenerative dementias. Am J Alzheimers Dis Other Demen 2010;25:547-55.
121. Roselli F, Hutzler P, Wegerich Y, et al. Disassembly of shank and homer synaptic clusters is driven by soluble β-amyloid(1-40) through divergent NMDAR-dependent signalling pathways. PLoS ONE 2009;4:e6011.
122. Koh JY, Yang LL, Cotman CW. β-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res 1990;533:315-20.
123. Mattson MP, Cheng B, Davis D, et al. β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 1992;12:376-89.
124. Floden AM. S. Li S, Combs CK. β-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor α and NMDA receptors. J Neurosci 2005;25:2566-75.
125. Song MS, Rauw G, Baker GB, et al. Memantine protects rat cortical cultured neurons against β-amyloid-induced toxicity by attenuating tau phosphorylation. Eur J Neurosci 2008;28:1989-2002.
126. Tremblay R, Chakravarthy B, Hewitt K, et al. Transient NMDA receptor inactivation provides long-term protection to cultured cortical neurons from a variety of death signals. J Neurosci 2000;20:7183-92.
127. Kamenetz F, Tomita T, Hsieh H, et al. APP processing and synaptic function. Neuron 2003;37:925-37.
128. Puzzo D, Privitera L, Fa M, et al. Endogenous amyloid β is necessary for hippocampal synaptic plasticity and memory. Ann Neurol 2011;69:819-30.
129. Cirrito JR, Yamada KA, Finn MB, et al. Synaptic activity regulates interstitial fluid amyloid-β levels in vivo. Neuron 2005;48:913-22.
130. Ting JT, Kelley BG, Lambert TJ, et al. Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms. Proc Natl Acad Sci U S A 2007;104:353-8.
131. Priller C, Bauer T, Mitteregger G, et al. Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 2006; 26:7212-21.
132. Kurup P, Zhang Y, Xu J, et al. Aβ-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61. J Neurosci 2010;30:5948-57.
133. Snyder EM, Nong Y, Almeida CG, et al. Regulation of NMDA receptor trafficking by amyloid-β. Nat Neurosci 2005;8:1051-8.
134. Braithwaite SP, Adkisson M, Leung J, et al. Regulation of NMDA receptor trafficking and function by striatal-enriched tyrosine phosphatase (STEP). Eur J Neurosci 2006;23:2847-56.
135. Kurup P, Zhang Y, Venkitaramani DV, et al. The role of STEP in Alzheimer's disease. Channels (Austin) 2010;4:347-50.
136. Zhang Y, Venkitaramani DV, Gladding CM, et al. The tyrosine phosphatase STEP mediates AMPA receptor endocytosis after metabotropic glutamate receptor stimulation. J Neurosci 2008;28: 10561-6.
137. Oh S, Hong HS, Hwang E, et al. Amyloid peptide attenuates the proteasome activity in neuronal cells. Mech Ageing Dev 2005;126: 1292-9.
138. Paul S, Nairn AC, Wang P, et al. NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling. Nat Neurosci 2003;6:34-42.
139. Ehrlich I, Klein M, Rumpel S, et al. PSD-95 is required for activitydriven synapse stabilization. Proc Natl Acad Sci U S A 2007;104:4176-81.
140. Kammermeier PJ. Surface clustering of metabotropic glutamate receptor 1 induced by long Homer proteins. BMC Neurosci 2006;7:1.
141. Gylys KH, Fein JA, Yang F, et al. Synaptic changes in Alzheimer's disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Am J Pathol 2004;165:1809-17.
142. Hayashi Y, Shi SH, Esteban JA, et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 2000;287:2262-7.
143. Poncer JC, Esteban JA, Malinow R. Multiple mechanisms for the potentiation of AMPA receptor-mediated transmission by α-Ca2+ / calmodulin-dependent protein kinase II. J Neurosci 2002;22: 4406-11.
144. Gu Z, Liu W, Yan Z. β-Amyloid impairs AMPA receptor trafficking and function by reducing Ca2+/calmodulin-dependent protein kinase II synaptic distribution. J Biol Chem 2009;284:10639-49.
145. Zhao D, Watson JB, Xie CW. Amyloid β prevents activation of calcium/ calmodulin-dependent protein kinase II and AMPA receptor phosphorylation during hippocampal long-term potentiation. J Neurophysiol 2004;92:2853-8.
146. Farr SA, Banks WA, Uezu K, et al. Antibody to β-amyloid protein increases acetylcholine in the hippocampus of 12 month SAMP8 male mice. Life Sci 2003;73:555-62.
147. Kar S, Seto D, Gaudreau P, et al. β-amyloid-related peptides inhibit potassium-evoked acetylcholine release from rat hippocampal slices. J Neurosci 1996;16:1034-40.
148. Bobich JA, Zheng Q, Campbell A. Incubation of nerve endings with a physiological concentration of Aβ1-42 activates CaV2.2(N-Type)-voltage operated calcium channels and acutely increases glutamate and noradrenaline release. J Alzheimers Dis 2004;6:243-55.
149. Li M, Smith CP. β-amyloid1-40 inhibits electrically stimulated release of [3H]norepinephrine and enhances the internal calcium response to low potassium in rat cortex: prevention with a free radical scavenger. Brain Res Bull 1996;39:299-303.
150. Arias C, Arrieta I, Tapia R. β-Amyloid peptide fragment 25-35 potentiates the calcium-dependent release of excitatory amino acids from depolarized hippocampal slices. J Neurosci Res 1995;41:561-6.
151. Abe K, Misawa M. The extracellular signal-regulated kinase cascade suppresses amyloidß protein-induced promotion of glutamate clearance in cultured rat cortical astrocytes. Brain Res 2003; 979: 179-87.
152. Rodriguez-Kern A, Gegelashvili M, Schousboe A, et al. β-amyloid and brain-derived neurotrophic factor, BDNF, up-regulate the expression of glutamate transporter GLT-1/EAAT2 via different signaling pathways utilizing transcription factor NF-kappaB. Neuro chem Int 2003;43:363-70.
153. Harris ME, Wang Y, Pedigo NW Jr, et al. Amyloid β peptide (25-35) inhibits Na+-dependent glutamate uptake in rat hippocampal astrocyte cultures. J Neurochem 1996;67:277-86.
154. Lauderback CM, Hackett JM, Huang FF, et al. The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer's disease brain: the role of Aβ1-42. J Neurochem 2001; 78:413-6.
155. Noda M, Nakanishi H, Akaike N. Glutamate release from microglia via glutamate transporter is enhanced by amyloid-β peptide. Neuroscience 1999;92:1465-74.
156. Pike CJ, Burdick D, Walencewicz AJ, et al. Neurodegeneration induced by β-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci 1993;13:1676-87.
157. Yankner BA. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron 1996;16:921-32.
158. Smith WW, Gorospe M, Kusiak JW. Signaling mechanisms underlying Aβ toxicity: potential therapeutic targets for Alzheimer's disease. CNS Neurol Disord Drug Targets 2006;5:355-61.
159. Roth KA. Caspases, apoptosis, and Alzheimer disease: causation, correlation, and confusion. J Neuropathol Exp Neurol 2001;60:829-38.
160. El Khoury J, Hickman SE, Thomas CA, et al. Scavenger receptormediated adhesion of microglia to β-amyloid fibrils. Nature 1996;382: 716-9.
161. Kuner P, Schubenel R, Hertel C. β-amyloid binds to p57NTR and activates NFκB in human neuroblastoma cells. J Neurosci Res 1998; 54:798-804.
162. Wang HY, Lee DH, Davis CB, et al. Amyloid peptide Aβ(1-42) binds selectively and with pM affinity to α7 nicotinic acetylcholine receptors. J Neurochem 2000;75:1155-61.
163. Yan SD, Chen X, Fu J, et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 1996;382:685-91.
164. Jhamandas JH, MacTavish D. Antagonist of the amylin receptor blocks β-amyloid toxicity in rat cholinergic basal forebrain neur-ons. J Neurosci 2004;24:5579-84.
165. Harkany T, Abraham I, Timmerman W, et al. β-amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis. Eur J Neurosci 2000;12:2735-45.
166. Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, et al. Neuroprotection by memantine against neurodegeneration induced by β-amyloid (1-40). Brain Res 2002;958:210-21.
167. Guo Q, Fu W, Sopher BL, et al. Increased vulnerability of hippo-campal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 1999;5:101-6.
168. Moechars D, Lorent K, Van Leuven F. Premature death in transgenic mice that overexpress a mutant amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. Neuroscience 1999; 91:819-30.
169. Alvarez G, Munoz-Montano JR, Satrustegui J, et al. Regulation of tau phosphorylation and protection against β-amyloid-induced neuro degeneration by lithium. Possible implications for Alzheimer's disease. Bipolar Disord 2002;4:153-65.
170. Brion JP, Anderton BH, Authelet M, et al. Neurofibrillary tangles and tau phosphorylation. Biochem Soc Symp 2001;(67):81-8.
171. Ferrer I, Gomez-Isla T, Puig B, et al. Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies. Curr Alzheimer Res 2005;2:3-18.
172. Zheng WH, Bastianetto S, Mennicken F, et al. Amyloid β peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience 2002;115:201-11.
173. Stoothoff WH, Johnson GV. Tau phosphorylation: physiological and pathological consequences. Biochim Biophys Acta 2005;1739: 280-97.
174. Rapoport M, Dawson HN, Binder LI, et al. Tau is essential to β-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A 2002;99: 6364-9.
175. Lesort M, Jope RS, Johnson GV. Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3β and Fyn tyrosine kinase. J Neurochem 1999;72:576-84.
176. Hernandez P, Lee G, Sjoberg M, et al. Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Aβ (25-35): involvement of lipid rafts. J Alzheimers Dis 2009;16:149-56.
177. Lee G, Thangavel R, Sharma VM, et al. Phosphorylation of tau by fyn: implications for Alzheimer's disease. J Neurosci 2004;24:2304-12.
178. Ittner LM, Ke YD, Delerue F, et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models. Cell 2010;142:387-97.
179. Liu F, Grundke-Iqbal I, Iqbal K, et al. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 2005;22:1942-50.
180. Liu F, Iqbal K, Grundke-Iqbal I, et al. Dephosphorylation of tau by protein phosphatase 5: impairment in Alzheimer's disease. J Biol Chem 2005;280:1790-6.
181. Gong CX, Shaikh S, Wang JZ, et al. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem 1995;65:732-8.
182. Sontag E, Luangpirom A, Hladik C, et al. Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol 2004; 63: 287-301.
183. Vogelsberg-Ragaglia V, Schuck T, Trojanowski JQ, et al. PP2A mRNA expression is quantitatively decreased in Alzheimer's disease hippocampus. Exp Neurol 2001;168:402-12.
184. Bennecib M, Gong CX, Grundke-Iqbal I, et al. Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356. FEBS Lett 2001;490:15-22.
185. Gong CX, Lidsky T, Wegiel J, et al. Phosphorylation of microtubuleassociated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease. J Biol Chem 2000;275:5535-44.
186. Qian W, Shi J, Yin X, et al. PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3β. J Alzheimers Dis 2010; 19:1221-9.
187. Pei JJ, Gong CX, An WL, et al. Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease. Am J Pathol 2003;163:845-58.
188. Adamec E, Mercken M, Beermann ML, et al. Acute rise in the concentration of free cytoplasmic calcium leads to dephosphorylation of the microtubule-associated protein tau. Brain Res 1997;757:93-101.
189. Fleming LM, Johnson GV. Modulation of the phosphorylation state of tau in situ: the roles of calcium and cyclic AMP. Biochem J 1995;309:41-7.
190. Liang Z, Liu F, Iqbal K, et al. Dysregulation of tau phosphorylation in mouse brain during excitotoxic damage. J Alzheimers Dis 2009; 17: 531-9.
191. Cotman CW, Poon WW, Rissman RA, et al. The role of caspase cleavage of tau in Alzheimer disease neuropathology. J Neuropathol Exp Neurol 2005;64:104-12.
192. 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 U S A 2003;100:10032-7.
193. Rissman RA, Poon WW, Blurton-Jones M, et al. Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 2004;114:121-30.
194. Liu MC, Kobeissy F, Zheng W, et al. Dual vulnerability of tau to calpains and caspase-3 proteolysis under neurotoxic and neurodegenerative conditions. ASN Neuro 2011;3:e00051.
195. Park SY, Ferreira A. The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates β amyloidinduced neurodegeneration. J Neurosci 2005;25:5365-75.
196. Raynaud F, Marcilhac A. Implication of calpain in neuronal apoptosis. A possible regulation of Alzheimer's disease. FEBS J 2006;273: 3437-43.
197. Amadoro G, Ciotti MT, Costanzi M, et al. NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Proc Natl Acad Sci U S A 2006;103:2892-7.
198. Kornhuber J, Weller M. Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry 1997;41:135-44.
199. Doraiswamy PM. The role of the N-methyl-D-aspartate receptor in Alzheimer's disease: therapeutic potential. Curr Neurol Neurosci Rep 2003;3:373-8.
200. Farlow MR. NMDA receptor antagonists. A new therapeutic approach for Alzheimer's disease. Geriatrics 2004;59:22-7.
201. Sonkusare SK, Kaul CL, Ramarao P. Dementia of Alzheimer's disease and other neurodegenerative disorders-memantine, a new hope. Pharmacol Res 2005;51:1-17.
202. Wenk GL, Parsons CG, Danysz W. Potential role of N-methyl-D aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine. Behav Pharmacol 2006;17: 411-24.
203. Lipton SA, Chen HS. Paradigm shift in NMDA receptor drug development. Expert Opin Ther Targets 2005;9:427-9.
204. Herrmann N, Li A, Lanctot K. Memantine in dementia: a review of the current evidence. Expert Opin Pharmacother 2011;12:787-800.
205. Parsons CG, Gilling K. Memantine as an example of a fast, voltagedependent, open channel N-methyl-D-aspartate receptor blocker. Methods Mol Biol 2007;403:15-36.
206. Rao VL, Dogan A, Todd KG, et al. Neuroprotection by memantine, a non-competitive NMDA receptor antagonist after traumatic brain injury in rats. Brain Res 2001;911:96-100.
207. Rammes G, Hasenjager A, Sroka-Saidi K, et al. Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 meta-botropic glutamate receptors in mediating the synaptotoxic effects of β-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices. Neuropharmacology 2011;60:982-90.
208. Martinez-Coria H, Green KN, Billings LM, et al. Memantine improves cognition and reduces Alzheimer's-like neuropathology in transgenic mice. Am J Pathol 2010;176:870-80.
209. Minkeviciene R, Banerjee P, Tanila H. Memantine improves spatial learning in a transgenic mouse model of Alzheimer's disease. J Pharmacol Exp Ther 2004;311:677-82.
210. Van Dam D, De Deyn PP. Cognitive evaluation of disease-modifying efficacy of galantamine and memantine in the APP23 model. Eur Neuropsychopharmacol 2006;16:59-69.
211. Dong H, Yuede CM, Coughlan C, et al. Effects of memantine on neuronal structure and conditioned fear in the Tg2576 mouse model of Alzheimer's disease. Neuropsychopharmacology 2008;33: 3226-36.
212. Alley GM, Bailey JA, Chen D, et al. Memantine lowers amyloid-β peptide levels in neuronal cultures and in APP/PS1 transgenic mice. J Neurosci Res 2010;88:143-54.
213. Ray B, Banerjee PK, Greig NH, et al. Memantine treatment decreases levels of secreted Alzheimer's amyloid precursor protein (APP) and Aβ peptide in the human neuroblastoma cells. Neurosci Lett 2010;470:1-5.
214. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-tosevere Alzheimer's disease. N Engl J Med 2003;348:1333-41.
215. van Dyck CH, Tariot PN, Meyers B, et al. A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease. Alzheimer Dis Assoc Disord 2007;21:136-43.
216. Winblad B, Jones RW, Wirth Y, et al. Memantine in moderate to severe Alzheimer's disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord 2007;24:20-7.
217. Bakchine S, Loft H. Memantine treatment in patients with mild to moderate Alzheimer's disease: results of a randomised, doubleblind, placebo-controlled 6-month study. J Alzheimers Dis 2007;11: 471-9.
218. Schneider LS, Dagerman KS, Higgins JP, et al. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol 2011; 68:991-8.
219. Lipton SA. Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci 2007;8:803-8.