Medical academic journalMedical academic journalМедицинский академический журнал1608-41012687-1378Eco-Vector977210.17816/MAJ14142-51ArticlesСтатьиReview ArticleMECHANISMS OF LONG TERM POTENTIATION IMPAIRMENT IN ALZHEIMER’S DESEASEМЕХАНИЗМЫ НАРУШЕНИЯ ДОЛГОВРЕМЕННОЙ ПОТЕНЦИАЦИИ ПРИ БОЛЕЗНИ АЛЬЦГЕЙМЕРАMukhinV NМухинВалерий Николаевич

к. м. н., старший научный сотрудник физиологического отдела им. И. П. Павлова

Valery.Mukhin@gmail.comKlimenkoV MКлименкоВиктор Матвеевич

д. м. н., профессор, заведующий физиологического отдела им. И. П. Павлова

Institute of Experimental Medicine of the NorthWest Branch of the Russian Academy of Medical SciencesНаучно-исследовательский институт экспериментальной медицины СЗО РАМН15032014141VOL 14, NO1 (2014)ТОМ 14, №1 (2014)425103092018Copyright ©; 2014, Mukhin V.N., Klimenko V.M.Copyright ©; 2014, Мухин В.Н., Клименко В.М.2014Mukhin V.N., Klimenko V.M.Мухин В.Н., Клименко В.М.http://creativecommons.org/licenses/by/4.0https://journals.eco-vector.com/MAJ/article/view/9772

Long term potentiation of synaptic strength (LTP) is an important neurophysiological mechanism of formation of declarative memory engram. Declarative memory disorder is a genuine symptom and obligate diagnostic criterion of Alzheimer’s disease. Che of pathophysiological components of such disorder is NMDA-dependent LTP impairment. To date, the scientific literature has accumulated data on the pathogenetic mechanisms of this impairment. Further study of pathogenesis of the declarative memory disorder in Alzheimer’s desease and development of ways to treat the disease requires summarizing of the data. This is the purpose of this literature review.

Долговременная потенциация синаптического проведения (ДВП) - один из важнейших нейрофизиологических механизмов формирования энграмм декларативной памяти. Нарушение декларативной памяти - генуинный признак и обязательный диагностический критерий болезни Альцгеймера. Среди патофизиологических компонентов нарушения декларативной памяти - подавление NMDA-зависимой ДВП. К настоящему времени в научной литературе накоплены сведения о патогенетических механизмах такого подавления. Дальнейшее изучение патогенеза нарушения декларативной памяти при болезни Альцгеймера и разработка средств лечения требуют обобщения и систематизации этих сведений, что и является целью данной статьи.

Alzheimer’s diseasedementiamemorylong term potentiationβ-amyloidNMDA receptormicroglianeuroimmune interactionsболезнь Альцгеймерапамятьдолговременная потенциацияβ-амилоидNMDA-рецептормикроглиянейроиммунные взаимодействияCavus I., Teyler T. Two forms of long-term potentiation in area CA1 activate different signal transduction cascades // J. Neurophysiol.- 1996.- Vol. 76 (5).- Р. 3038-3047.Luscher C., Malenka R. C. NMDA Receptor-Dependent Long-Term Potentiation and Long-Term Depression (LTP/LTD) // Cold Spring Harb Perspect Biol.- 2012.- Vol. 4 (6).Lynch M. A. Long-Term Potentiation and Memory // Physiol Rev.- 2004.- Vol. 84 (1).- Р. 87-136.Whitlock J. R., Heynen A. J., Shuler M. G., Bear M. F. Learning Induces Long-Term Potentiation in the Hippocampus // Science.- 2006.- Vol. 313 (5790).- Р. 1093-1097.Rogan M. T., Staubli U. V., LeDoux J. E. Fear conditioning induces associative long-term potentiation in the amygdala // Nature.- 1997.- Vol. 390 (6660).- Р. 604-607.Rowan M. J., Klyubin I., Wang Q., Anwyl R. Synaptic plasticity disruption by amyloid beta protein: modulation by potential Alzheimer s disease modifying therapies // Biochem. Soc. Trans.- 2005.- Vol. 33 (Pt 4).- Р. 563-567.Selkoe D. J. Alzheimer’s Disease Is a Synaptic Failure // Science.- 2002.- Vol. 298 (5594).- Р. 789-791.Battaglia F., Wang H.-Y., Ghilardi M. F. et al. Cortical Plasticity in Alzheimer s Disease in Humans and Rodents // Biological Psychiatry.- 2007.- Vol. 62 (12).- Р. 1405-1412.Koch G., Di Lorenzo F., Bonni S. et al. Impaired LTP-but not LTD-Like Cortical Plasticity in Alzheimer s Disease Patients // Journal of Alzheimer’s Disease.- 2012.- Vol. 31 (3).- Р. 593-599.Wei W., Nguyen L. N., Kessels H. W. et al. Amyloid beta from axons and dendrites reduces local spine number and plasticity // Nature Neuroscience.- 2010.- Vol. 13 (2).- Р. 190-196.Busciglio J., Gabuzda D. H., Matsudaira P., Yankner B. A. Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells // PNAS.- 1993.- Vol. 90 (5).- Р. 2092-2096.Koudinov A. R., Koudinova N. V. Alzheimer s soluble amyloid beta protein is secreted by HepG2 cells as an apolipoprotein // Cell Biol. Int.- 1997.- Vol. 21 (5).- Р. 265-271.Kamenetz F., Tomita T., Hsieh H. et al. APP processing and synaptic function // Neuron.- 2003.- Vol. 37 (6).- Р. 925-937.Koudinov A. R., Berezov T. T. Alzheimer s amyloid-beta (A beta) is an essential synaptic protein, not neurotoxic junk // Acta Neurobiol Exp (Wars).- 2004.- Vol. 64 (1).- Р. 71-79.Lesne S., Ali C., Gabriel C. et al. NMDA Receptor Activation Inhibits a-Secretase and Promotes Neuronal Amyloid-b Production // J. Neurosci.- 2005.- Vol. 25 (41).- Р. 9367-9377.Sweatt J. D. Mechanisms of Memory.- Academic Press, 2009.Duyckaerts C., Delatour B., Potier M.-C. Classification and basic pathology of Alzheimer disease // Acta Neuropathologica.- 2009.- Vol. 118 (1).- Р. 5-36.Cirrito J. R., Yamada K. A., Finn M. B. et al. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo // Neuron.- 2005.- Vol. 48 (6).- Р. 913-922.Cleary J. P., Walsh D. M., Hofmeister J. J. et al. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function // Nat. Neurosci.- 2005.- Vol. 8 (1).- Р. 79-84.Cullen W. K., Suh Y. H., Anwyl R., Rowan M. J. Block of LTP in rat hippocampus in vivo by beta-amyloid precursor protein fragments // Neuroreport.- 1997.- Vol. 8 (15).- Р. 3213-3217.Walsh D. M., Klyubin I., Fadeeva J. V. et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo // Nature.- 2002.- Vol. 416 (6880).- Р. 535-539.Wang H.-W., Pasternak J. F., Kuo H. et al. Soluble oligomers of b amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus // Brain Research.- 2002.- Vol. 924 (2).- Р. 133-140.Randall A.D., Witton J., Booth C. et al. The functional neurophysiology of the amyloid precursor protein (APP) processing pathway // Neuropharmacology.- 2010.- Vol. 59 (4-5).- Р. 243-267.Chen Q.-S., Wei W.-Z., Shimahara T., Xie C.-W. Alzheimer Amyloid b-Peptide Inhibits the Late Phase of Long-Term Potentiation through Calcineurin-Dependent Mechanisms in the Hippocampal Dentate Gyrus // Neurobiology of Learning and Memory.- 2002.- VT 77 (3).- Р. 354-371.Holscher C., Gengler S., Gault V. A. et al. Soluble beta-amyloid[25-35] reversibly impairs hippocampal synaptic plasticity and spatial learning // Europ. J. of Pharmacology.- 2007.- Vol. 561 (1-3).- Р. 85-90.Zhang J.-M., Wu M.-N., Qi J.-S., Qiao J.-T. Amyloid b-protein fragment 31-35 suppresses long-term potentiation in hippocampal CA1 region of rats in vivo // Synapse.- 2006.- Vol. 60 (4).- Р. 307-313.Wu J., Anwyl R., Rowan M. J. beta-Amyloid-(1-40) increases long-term potentiation in rat hippocampus in vitro // Eur. J. Pharmacol.- 1995.- Vol. 284 (3).- Р. R1-3.Wu J., Anwyl R., Rowan M. beta-Amyloid selectively augments NMDA receptor-mediated synaptic transmission in rat hippocampus // Neuroreport.- 1995.- Vol. 6 (17).- Р. 2409-2413.Wang Q., Wu J., Rowan M. J., Anwyl R. b-amyloid inhibition of long-term potentiation is mediated via tumor necrosis factor // Europ. J. of Neuroscience.- 2005.- Vol. 22 (11).- Р. 2827-2832.Akiyama H., Barger S., Barnum S. et al. Inflammation and Alzheimer s disease // Neurobiology of Aging.- 2000.- Vol. 21 (3).- Р. 383-421.Lue L.-F., Walker D. G., Brachova L. et al. Involvement of Microglial Receptor for Advanced Glycation Endproducts (RAGE) in Alzheimer s Disease: Identification of a Cellular Activation Mechanism // Experimental Neurology.- 2001.- Vol. 171 (1).- Р. 29-45.Yan S. D., Chen X., Fu J. et al. RAGE and amyloid-b peptide neurotoxicity in Alzheimer s disease // Nature.- 1996.- Vol. 382 (6593).- Р. 685-691.Rouhiainen A., Kuja-Panula J., Tumova S., Rauvala H. RAGE-Mediated Cell Signaling. Calcium-Binding Proteins and RAGE / ed. C. W. Heizmann.- Humana Press, 2013.- Р. 239-263.Yan S., Chen X., Walker D. et al. RAGE: A Potential Target for A-beta -Mediated Cellular Perturbation in Alzheimers Disease // Current Molecular Med.- 2007.- Vol. 7 (8).- Р. 735-742.Bachstetter A. D., Xing B., de Almeida L. et al. Microglial p38a MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Ab) // J. Neuroinflammation.- 2011.- Vol. 8 (1).- Р. 1-12.Pyo H., Jou I., Jung S. et al. Mitogen-activated protein kinases activated by lipopolysaccharide and beta-amyloid in cultured rat microglia // Neuroreport.- 1998.- Vol. 9 (5).- Р. 871-874.Fang F., Lue L.-F., Yan S. et al. RAGE-dependent signaling in microglia contributes to neuroinflammation, Ab accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease // FASEB J.- 2010.- Vol. 24 (4).- Р. 1043-1055.Block M. L., Hong J.-S. Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism // Progress in Neurobiology.- 2005.- Vol. 76 (2).- Р. 77-98.MacManus A., Ramsden M., Murray M. et al. Enhancement of 45Ca2+ influx and voltage-dependent Ca2+ channel activity by b-Amyloid-(1-40) in rat cortical synaptosomes and cultured cortical neurons modulation by the proinflammatory cytokine interleukin-1b // J. Biol. Chem.- 2000.- Vol. 275 (7).- Р. 4713-4718.Silei V., Fabrizi C., Venturini G. et al. Activation of microglial cells by PrP and b-amyloid fragments raises intracellular calcium through L-type voltage sensitive calcium channels // Brain Research.- 1999.- Vol. 818 (1).- Р. 168-170.Thellung S., Villa V., Corsaro A. et al. ERK1/2 and p38 MAP kinases control prion protein fragment 90-231-induced astrocyte proliferation and microglia activation // Glia.- 2007.- Vol. 55 (14).- Р. 1469-1485.Freir D. B., Herron C. E. Inhibition of l-type voltage dependent calcium channels causes impairment of long-term potentiation in the hippocampal CA1 region in vivo // Brain Research.- 2003.- Vol. 967 (1-2).- Р. 27-36.Rovira C., Arbez N., Mariani J. Abeta(25-35) and Abeta(1-40) act on different calcium channels in CA1 hippocampal neurons // Biochem. Biophys. Res. Commun.- 2002.- Vol. 296 (5).- Р. 1317-1321.Kettenmann H., Hanisch U.-K., Noda M., Verkhratsky A. Physiology of Microglia // Physiol Rev.- 2011.- Vol. 91 (2).- Р. 461-553.Bartus R. T., Dean R. L. 3rd, Beer B., Lippa A. S. The cholinergic hypothesis of geriatric memory dysfunction // Science.- 1982.- Vol. 217 (4558).- Р. 408-414.Minghetti L., Carnevale D., Simone R. D. Microglia-Neuron Interaction in Inflammatory and Degenerative Diseases: Role of Cholinergic and Noradrenergic Systems // CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders).- 2007.- Vol. 6 (6).- Р. 388-397.Bianca V. D., Dusi S., Bianchini E. et al. Beta-amyloid activates the 02-forming NADPH oxidase in microglia, monocytes, and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer’s disease // J. Biol. Chem.- 1999.- Vol. 274 (22).- Р. 15493-15499.Ii M., Sunamoto M., Ohnishi K., Ichimori Y. b-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity // Brain Research.- 1996.- Vol. 720 (1-2).- Р. 93-100.Meda L., Cassatella M. A., Szendrei G. I. et al. Activation of microglial cells by b-amyloid protein and interferon-g // Nature.- 1995.- Vol. 374 (6523).- Р. 647-650.Qin L., Liu Y., Cooper C. et al. Microglia enhance b-amyloid peptide-induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species // Journal of Neurochemistry.- 2002.- Vol. 83 (4).- Р. 973-983.Wang Q., Rowan M. J., Anwyl R. b-Amyloid-Mediated Inhibition of NMDA Receptor-Dependent Long-Term Potentiation Induction Involves Activation of Microglia and Stimulation of Inducible Nitric Oxide Synthase and Superoxide // J. Neurosci.- 2004.- Vol. 24 (27).- Р. 6049-6056.Alkam T., Nitta A., Mizoguchi H. et al. Restraining tumor necrosis factor-alpha by thalidomide prevents the Amyloid beta-induced impairment of recognition memory in mice // Behavioural Brain Research.- 2008.- Vol. 189 (1).- Р. 100-106.Wang Q., Walsh D. M., Rowan M. J. et al. Block of Long-Term Potentiation by Naturally Secreted and Synthetic Amyloid b-Peptide in Hippocampal Slices Is Mediated via Activation of the Kinases c-Jun N-Terminal Kinase, Cyclin-Dependent Kinase 5, and p38 Mitogen-Activated Protein Kinase as well as Metabotropic Glutamate Receptor Type 5 // J. Neurosci.- 2004.- Vol. 24 (13).- Р. 3370-3378.Pickering M., Cumiskey D., O’Connor J. J. Actions of TNF-a on glutamatergic synaptic transmission in the central nervous system // Exp. Physiol.- 2005.- Vol. 90 (5).- Р. 663-670.Piers T. M., Kim D. H., Kim B. C. et al. Translational concepts of mGluR5 in synaptic diseases of the brain. Front. Pharmacol.- 2012.- Vol. 3.- Р. 199.Mayford M., Siegelbaum S. A., Kandel E. R. Synapses and Memory Storage // Cold Spring Harb Perspect Biol.- 2012.- Vol. 4 (6).Kessels H. W., Nabavi S., Malinow R. Metabotropic NMDA receptor function is required for b-amyloid-induced synaptic depression // PNAS.- 2013.Nong Y., Huang Y.-Q., Ju W. et al. Glycine binding primes NMDA receptor internalization // Nature.- 2003.- Vol. 422 (6929).- Р. 302-307.Snyder E. M., Philpot B. D., Huber K. M. et al. Internalization of ionotropic glutamate receptors in response to mGluR activation // Nature Neuroscience.- 2001.- Vol. 4 (11).- Р. 1079-1085.Dewachter I., Ris L., Jaworski T. et al. GSK3b, a centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory phosphorylation at Serine-9 // Neurobiology of Disease.- 2009.- Vol. 35 (2).- Р. 193-200.Snyder E. M., Nong Y., Almeida C. G. et al. Regulation of NMDA receptor trafficking by amyloid-beta // Nat. Neurosci.- 2005.- Vol. 8 (8).- Р. 1051-1058.Jo J., Whitcomb D. J., Olsen K. M. et al. Ab(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3b // Nat. Neurosci.- 2011.- Vol. 14 (5).- Р. 545-547.Stornetta R. L., Zhu J. J. Ras and Rap Signaling in Synaptic Plasticity and Mental Disorders // Neuroscientist.- 2011.- Vol. 17 (1).- Р. 54-78.Townsend M., Mehta T., Selkoe D. J. Soluble Ab Inhibits Specific Signal Transduction Cascades Common to the Insulin Receptor Pathway // J. Biol. Chem.- 2007.- Vol. 282 (46).- Р. 33305-33312.Kurup P., Zhang Y., Xu J. et al. Ab-Mediated NMDA Receptor Endocytosis in Alzheimer s Disease Involves Ubiquitination of the Tyrosine Phosphatase STEP61 // J. Neurosci.- 2010.- Vol. 30 (17).- Р. 5948-5957.Tseng B. P., Green K. N., Chan J. L. et al. Ab inhibits the proteasome and enhances amyloid and tau accumulation // Neurobiology of Aging.- 2008.- Vol. 29 (11).- Р. 1607-1618.Begley J. G., Duan W., Chan S. et al. Altered Calcium Homeostasis and Mitochondrial Dysfunction in Cortical Synaptic Compartments of Presenilin-1 Mutant Mice // Journal of Neurochemistry.- 1999.- Vol. 72 (3).- Р. 1030-1039.Mattson M. P., Cheng B., Davis D. et al. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity // J. Neurosci.- 1992.- Vol. 12 (2).- Р. 376-389.Sze C.-I., Bi H., Kleinschmidt-DeMasters B. K. et al. N-Methyl-d-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer’s disease // Journal of the Neurological Sciences.- 2001.- Vol. 182 (2).- Р. 151-159.Mattson M. P., Duan W., Pedersen W. A., Culmsee C. Neurodegenerative disorders and ischemic brain diseases // Apoptosis.- 2001.- Vol. 6 (1).- Р. 69-81.Murray F. E., Landsberg J. P., Williams R. J. et al. Elemental analysis of neurofibrillary tangles in Alzheimer s disease using proton-induced X-ray analysis // Ciba Found. Symp.- 1992.- Vol. 169.- Р. 201-210; discussion 210-216.Hernandez C. M., Dineley K. T. a7 Nicotinic Acetylcholine Receptors in Alzheimer s Disease: Neuroprotective, Neurotrophic or Both? // Curr. Drug Targets.- 2012.- Vol. 13 (5).- Р. 613-622.Dineley K. T., Westerman M., Bui D. et al. b-Amyloid Activates the Mitogen-Activated Protein Kinase Cascade via Hippocampal a7 Nicotinic Acetylcholine Receptors:In Vitro and In Vivo Mechanisms Related to Alzheimer’s Disease // J. Neurosci.- 2001.- Vol. 21 (12).- Р. 4125-4133.Mehta T. K., Dougherty J. J., Wu J. et al. Defining pre-synaptic nicotinic receptors regulated by beta amyloid in mouse cortex and hippocampus with receptor null mutants // Journal of Neurochemistry.- 2009.- Vol. 109 (5).- Р. 1452-1458.Zhang Y.-J., Shi J.-M., Bai C.-J. et al. Intra-membrane Oligomerization and Extra-membrane Oligomerization of Amyloid-b Peptide Are Competing Processes as a Result of Distinct Patterns of Motif Interplay // J. Biol. Chem.- 2012.- Vol. 287 (1).- Р. 748-756.Kayed R., Pensalfini A., Margol L. et al. Annular Protofibrils Are a Structurally and Functionally Distinct Type of Amyloid Oligomer // J. Biol. Chem.- 2009.- Vol. 284 (7).- Р. 4230-4237.Kayed R., Sokolov Y., Edmonds B. et al. Permeabilization of Lipid Bilayers Is a Common Conformation-dependent Activity of Soluble Amyloid Oligomers in Protein Misfolding Diseases // J. Biol. Chem.- 2004.- Vol. 279 (45).- Р. 46363-46366.Small D. H., Maksel D., Kerr M. L. et al. The b-amyloid protein of Alzheimer’s disease binds to membrane lipids but does not bind to the a7 nicotinic acetylcholine receptor // Journal of Neurochemistry.- 2007.- Vol. 101 (6).- Р. 1527-1538.Sokolov Y., Kozak J. A., Kayed R. et al. Soluble Amyloid Oligomers Increase Bilayer Conductance by Altering Dielectric Structure // J. Gen Physiol.- 2006.- Vol. 128 (6).- Р. 637-647.Ekinci F. J., Malik K. U., Shea T. B. Activation of the L Voltage-sensitive Calcium Channel by Mitogen-activated protein (MAP) kinase following exposure of neuronal cells to b-amyloid kinase mediates b-amyloid-induced neurodegeneration // J. Biol. Chem.- 1999.- Vol. 274 (42).- Р. 30322-30327.Ueda K., Shinohara S., Yagami T. et al. Amyloid b Protein Potentiates Ca2+ Influx Through L-Type Voltage-Sensitive Ca2+ Channels: A Possible Involvement of Free Radicals // Journal of Neurochemistry.- 1997.-Vol. 68 (1).- Р. 265-271.Lauren J., Gimbel D. A., Nygaard H. B. et al. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-|[bgr]| oligomers // Nature.- 2009.- Vol. 457 (7233).- Р. 1128-1132.You H., Tsutsui S., Hameed S. et al. Ab neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-d-aspartate receptors // PNAS.- 2012.- Vol. 109 (5).- Р. 1737-1742.Stys P. K., You H., Zamponi G. W. Copper-dependent regulation of NMDA receptors by cellular prion protein: implications for neurodegenerative disorders // The Journal of Physiology.- 2012.- Vol. 590 (6).- Р. 1357-1368.Sala C., Sheng M. The fyn art of N-methyl-d-aspartate receptor phosphorylation // PNAS.- 1999.- Vol. 96 (2).- Р. 335-337.Um J. W., Strittmatter S. M. Amyloid-b induced signaling by cellular prion protein and Fyn kinase in Alzheimer disease // Prion.- 2013.- Vol. 7 (1).- Р. 37-41.Gimbel D. A., Nygaard H. B., Coffey E. E. et al. Memory Impairment in Transgenic Alzheimer Mice Requires Cellular Prion Protein // J. Neurosci.- 2010.- Vol. 30 (18).- Р. 6367-6374.Ho G. J., Hashimoto M., Adame A. et al. Altered p59Fyn kinase expression accompanies disease progression in Alzheimer s disease: implications for its functional role // Neurobiology of Aging.- 2005.- Vol. 26 (5).- Р. 625-635.Shirazi S. K., Wood J. G. The protein tyrosine kinase, fyn, in Alzheimer s disease pathology // Neuroreport.- 1993.- Vol. 4 (4).- Р. 435-437.Barry A.E., Klyubin I., Donald J. M. M. et al. Alzheimers Disease Brain-Derived Amyloid-b-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein // J. Neurosci.- 2011.- Vol. 31 (20).- Р. 7259-7263.Cisse M., Sanchez P. E., Kim D. H. et al. Ablation of Cellular Prion Protein Does Not Ameliorate Abnormal Neural Network Activity or Cognitive Dysfunction in the J20 Line of Human Amyloid Precursor Protein Transgenic Mice // J. Neurosci.- 2011.- Vol. 31 (29).- Р. 10427-10431.Forloni G., Balducci C. b-amyloid oligomers and prion protein: Fatal attraction? // Prion.- 2011.- Vol. 5 (1).- Р. 10-15.Origlia N., Righi M., Capsoni S. et al. Receptor for Advanced Glycation End Product-Dependent Activation of p38 Mitogen-Activated Protein Kinase Contributes to Amyloid-b-Mediated Cortical Synaptic Dysfunction // J. Neurosci.- 2008.- Vol. 28 (13).- Р. 3521-3530.Li S., Jin M., Koeglsperger T. et al. Soluble Ab Oligomers Inhibit Long-Term Potentiation through a Mechanism Involving Excessive Activation of Extrasynaptic NR2B-Containing NMDA Receptors // J. Neurosci.- 2011.- Vol. 31 (18).- Р. 6627-6638.Hruska M., Dalva M. B. Ephrin regulation of synapse formation, function and plasticity // Molecular and Cellular Neuroscience.- 2012.- Vol. 50 (1).- Р. 35-44.Buchert M., Schneider S., Meskenaite V. et al. The Junction-associated Protein AF-6 Interacts and Clusters with Specific Eph Receptor Tyrosine Kinases at Specialized Sites of Cell-Cell Contact in the Brain // J. Cell Biol.- 1999.- Vol. 144 (2).- Р. 361-371.Henkemeyer M., Itkis O. S., Ngo M. et al. Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus // J. Cell Biol.- 2003.- Vol. 163 (6).- Р. 1313-1326.Dalva M. B., Takasu M. A., Lin M. Z. et al. EphB Receptors Interact with NMDA Receptors and Regulate Excitatory Synapse Formation // Cell.- 2000.- Vol. 103 (6).- Р. 945-956.Takasu M. A., Dalva M. B., Zigmond R. E., Greenberg M. E. Modulation of NMDA Receptor- Dependent Calcium Influx and Gene Expression Through EphB Receptors // Science.- 2002.- Vol. 295 (5554).- Р. 491-495.Cisse M., Halabisky B., Harris J. et al. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model // Nature.- 2011.- Vol. 469 (7328).- Р. 47-52.Simon A. M., de Maturana R. L., Ricobaraza A. et al. Early Changes in Hippocampal Eph Receptors Precede the Onset of Memory Decline in Mouse Models of Alzheimer’s Disease // Journal of Alzheimer’s Disease.- 2009.- Vol. 17 (4).- Р. 773-786.Shankar G. M., Bloodgood B. L., Townsend M. et al. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway // J. Neurosci.- 2007.- Vol. 27 (11).- Р. 2866-2875.Ma T., Hoeffer C. A., Capetillo-Zarate E. et al. Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimer’s Disease // PLoS Che.- 2010.- Vol. 5 (9).Antion M. D., Merhav M., Hoeffer C. A. et al. Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity // Learn Mem.- 2008.- Vol. 15 (1).- Р. 29-38.Banko J. L., Merhav M., Stern E. et al. Behavioral alterations in mice lacking the translation repressor 4E-BP2 // Neurobiol. Learn Mem.- 2007.- Vol. 87 (2).- Р. 248-256.Banko J. L., Poulin F., Hou L. et al. The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus // J. Neurosci.- 2005.- Vol. 25 (42).- Р. 9581-9590.Blundell J., Kouser M., Powell C. M. Systemic inhibition of mammalian target of rapamycin inhibits fear memory reconsolidation // Neurobiol Learn Mem.- 2008.- Vol. 90 (1).- Р. 28-35.Gafford G. M., Parsons R. G., Helmstetter F. J. Consolidation and reconsolidation of contextual fear memory requires mammalian target of rapamycin-dependent translation in the dorsal hippocampus // Neuroscience.- 2011.- Vol. 182.- Р. 98-104.Hoeffer C. A., Cowansage K. K., Arnold E. C. Inhibition of the interactions between eukaryotic initiation factors 4E and 4G impairs long-term associative memory consolidation but not reconsolidation // Proc. Natl. Acad. Sci. U.S.A.- 2011.- Vol. 108 (8).- Р. 3383-3388.Hoeffer C. A., Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease // Trends Neurosci.- 2010.- Vol. 33 (2).- Р. 67-75.Stoica L., Zhu P. J., Huang W. et al. Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage // Proc. Natl. Acad. Sci. U.S.A.- 2011.- Vol. 108 (9).- Р. 3791-3796.Zhu L.-Q., Wang S.-H., Liu D. et al. Activation of Glycogen Synthase Kinase-3 Inhibits Long-Term Potentiation with Synapse-Associated Impairments // J. Neurosci.- 2007.- Vol. 27 (45).- Р. 12211-12220.Hooper C., Markevich V., Plattner F. et al. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation // Europ. J. of Neuroscience.- 2007.- Vol. 25 (1).- Р. 81-86.Peineau S., Bradley C., Taghibiglou C. et al. The role of GSK-3 in synaptic plasticity // Brit. J. of Pharmacology.- 2008.- Vol. 153 (S1).- Р. S428-S437.Liao Y., Hung M.-C. Physiological regulation of Akt activity and stability // Am. J. Transl. Res.- 2010.- Vol. 2 (1).- Р. 19-42.Magrane J., Rosen K. M., Smith R. C. Intraneuronal b-Amyloid Expression Downregulates the Akt Survival Pathway and Blunts the Stress Response // J. Neurosci.- 2005.- Vol. 25 (47).- Р. 10960-10969.Taru H., Yoshikawa K., Suzuki T. Suppression of the caspase cleavage of b-amyloid precursor protein by its cytoplasmic phosphorylation // FEBS Letters.- 2004.- Vol. 567 (2-3).- Р. 248-252.D Amelio M., Cavallucci V., Cecconi F. Neuronal caspase-3 signaling: not only cell death // Cell Death & Differentiation.- 2010.- Vol. 17 (7).- Р. 1104-1114.