摘要
背景：阿尔茨海默病（AD）与关键脑丝裂原活化蛋白激酶（MAPK）信号级联的损伤有关，包括p38，c-Jun N末端激酶（JNK），ERK和Akt通路。载脂蛋白E4（ApoE4）是AD中最常见的遗传风险因子。 目的：研究MAPK信号通路在介导apoE4的病理作用中发挥作用的程度，并可通过实验操作逆转。 方法：使用来自幼稚和病毒处理的apoE3和apoE4靶向替代小鼠的海马组织的免疫印迹测定获得的MAPK信号传导途径因子的总水平和活化的测量。 结果：ApoE4小鼠显示出与应激相关的p38和JNK途径的强烈活化以及Akt活性的相应降低，其与GSK3β的激活和tau蛋白过度磷酸化相关。对ERK途径没有影响。我们先前已经证明了apoE4相关的病理学，即;通过利用表达VEGF的腺相关病毒上调VEGF水平，可以逆转Aβ的积累，过度磷酸化的tau，突触损伤和降低的VEGF水平。利用这种方法，我们评估了apoE4的AD标志和突触病理与相应的MAPK信号传导效应相关的程度。这表明通过VEGF治疗逆转apoE4驱动的病理学与p38和Akt相关作用的逆转相关。 结论：总之，这些结果表明p38和Akt通路在介导apoE4在海马中的AD相关病理学作用中起作用。
关键词: 阿尔茨海默病（AD），载脂蛋白E4（apoE4），VEGF，MAPK，信号传导，腺相关病毒，海马，靶向替代小鼠。
[1]
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82(12): 4245-9. (1985).
[2]
Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde. Clin Anat 8(6): 429-31. (1995).
[3]
Masliah E, Crews L, Hansen L. Synaptic remodeling during aging and in Alzheimer’s disease. J Alzheimers Dis 9(3)(Suppl.): 91-9. (2006).
[4]
Schwartz M, Deczkowska A. Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol 37(10): 668-79. (2016).
[5]
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele
and the risk of Alzheimer's disease in late onset families. Science
(New York, NY 261(5123): 921-3 (1993).
[6]
Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med 47: 387-400. (1996).
[7]
Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43(8): 1467-72. (1993).
[8]
Liu DS, Pan XD, Zhang J, Shen H, Collins NC, Cole AM, et al. APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice. Mol Neurodegener 10: 7. (2015).
[9]
Schindler S, Gratia P, Mullenberger G, Arendt J. Adenosarcoma and other uterine sarcomas. Bulletin de la Societe des sciences medicales du Grand-Duche de Luxembourg 134(2): 27-30. (1997).
[10]
Mahley RW, Huang Y. Apolipoprotein e sets the stage: response to injury triggers neuropathology. Neuron 76(5): 871-85. (2012).
[11]
Kutner KC, Erlanger DM, Tsai J, Jordan B, Relkin NR. Lower
cognitive performance of older football players possessing
apolipoprotein E epsilon4. Neurosurgery 47(3): 651-7, 57-8 (2000).
[12]
Peila R, Rodriguez BL, Launer LJ, Honolulu-Asia Aging S. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia aging study. Diabetes 51(4): 1256-62. (2002).
[13]
Michaelson DM. APOE epsilon4: the most prevalent yet understudied risk factor for Alzheimer’s disease. Alzheimer’s Dementia: J Alzheimer’s Assoc 10(6): 861-8. (2014).
[14]
Ungar L, Altmann A, Greicius MD. Apolipoprotein E, gender, and Alzheimer’s disease: an overlooked, but potent and promising interaction. Brain Imaging Behav 8(2): 262-73. (2014).
[15]
Bar R, Boehm-Cagan A, Luz I, Kleper-Wall Y, Michaelson DM. The effects of apolipoprotein E genotype, alpha-synuclein deficiency, and sex on brain synaptic and Alzheimer’s disease-related pathology. Alzheimers Dement (Amst) 10: 1-11. (2018).
[16]
Kim EK, Choi EJ. Compromised MAPK signaling in human diseases: an update. Arch Toxicol 89(6): 867-82. (2015).
[17]
Yu Q, Du F, Douglas JT, Yu H, Yan SS, Yan SF. Mitochondrial dysfunction triggers synaptic deficits via activation of p38 map kinase signaling in differentiated Alzheimer’s disease trans-mitochondrial cybrid cells. J Alzheimers Dis 59(1): 223-39. (2017).
[18]
Zhu X, Lee HG, Raina AK, Perry G, Smith MA. The role of mitogen-activated protein kinase pathways in Alzheimer’s disease. Neurosignals 11(5): 270-81. (2002).
[19]
Munoz L, Ammit AJ. Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology 58(3): 561-8. (2010).
[20]
Hensley K, Floyd RA, Zheng NY, Nael R, Robinson KA, Nguyen X, et al. p38 kinase is activated in the Alzheimer’s disease brain. J Neurochem 72(5): 2053-8. (1999).
[21]
Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 1773(8): 1358-75. (2007).
[22]
Mehan S, Meena H, Sharma D, Sankhla R. JNK: a stress-activated protein kinase therapeutic strategies and involvement in Alzheimer’s and various neurodegenerative abnormalities. J Mol Neurosci 43(3): 376-90. (2011).
[23]
Hoe HS, Harris DC, Rebeck GW. Multiple pathways of apolipoprotein E signaling in primary neurons. J Neurochem 93(1): 145-55. (2005).
[24]
Okazawa H, Estus S. The JNK/c-Jun cascade and Alzheimer’s disease. Am J Alzheimers Dis Other Demen 17(2): 79-88. (2002).
[25]
Takashima A. GSK-3 is essential in the pathogenesis of Alzheimer’s disease. J Alzheimers Dis 9(3)(Suppl.): 309-17. (2006).
[26]
Zhang Y, Huang NQ, Yan F, Jin H, Zhou SY, Shi JS, et al. Diabetes mellitus and Alzheimer’s disease: GSK-3beta as a potential link. Behav Brain Res 339: 57-65. (2018).
[27]
Morroni F, Sita G, Tarozzi A, Rimondini R, Hrelia P. Early effects of Abeta1-42 oligomers injection in mice: involvement of PI3K/Akt/GSK3 and MAPK/ERK1/2 pathways. Behav Brain Res 314: 106-15. (2016).
[28]
Sun J, Nan G. The extracellular signal-regulated kinase 1/2 pathway in neurological diseases: a potential therapeutic target. (Review) Intern J Mol Med 39(6): 1338-46. (2017).
[29]
Kirouac L, Rajic AJ, Cribbs DH, Padmanabhan J. Activation of Ras-ERK signaling and GSK-3 by amyloid precursor protein and amyloid beta facilitates neurodegeneration in Alzheimer’s disease. eNeuro 4(2) (2017).
[30]
Gan X, Wu L, Huang S, Zhong C, Shi H, Li G, et al. Oxidative stress-mediated activation of extracellular signal-regulated kinase contributes to mild cognitive impairment-related mitochondrial dysfunction. Free Radic Biol Med 75: 230-40. (2014).
[31]
Lau D, Bengtson CP, Buchthal B, Bading H. BDNF reduces toxic extrasynaptic nmda receptor signaling via synaptic NMDA receptors and nuclear-calcium-induced transcription of inhba/activin A. Cell Reports 12(8): 1353-66. (2015).
[32]
Maezawa I, Maeda N, Montine TJ, Montine KS. Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice. J Neuroinflammation 3: 10. (2006).
[33]
DeKroon R, Robinette JB, Hjelmeland AB, Wiggins E, Blackwell M, Mihovilovic M, et al. APOE4-VLDL inhibits the HDL-activated phosphatidylinositol 3-kinase/Akt Pathway via the phosphoinositol phosphatase SHIP2. Circ Res 99(8): 829-36. (2006).
[34]
Ong QR, Chan ES, Lim ML, Cole GM, Wong BS. Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice. Sci Rep 4: 3754. (2014).
[35]
Salomon-Zimri S, Boehm-Cagan A, Liraz O, Michaelson DM. Hippocampus-related cognitive impairments in young apoE4 targeted replacement mice. Neurodegener Dis 13(2-3): 86-92. (2014).
[36]
Liraz O, Boehm-Cagan A, Michaelson DM. ApoE4 induces Abeta42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice. Mol Neurodegener 8: 16. (2013).
[37]
Gilat-Frenkel M, Boehm-Cagan A, Liraz O, Xian X, Herz J, Michaelson DM. Involvement of the Apoer2 and Lrp1 receptors in mediating the pathological effects of ApoE4 in vivo. Curr Alzheimer Res 11(6): 549-57. (2014).
[38]
Salomon-Zimri S, Glat MJ, Barhum Y, Luz I, Boehm-Cagan A, Liraz O, et al. Reversal of ApoE4-driven brain pathology by vascular endothelial growth factor treatment. J Alzheimers Dis 53(4): 1443-58. (2016).
[39]
Liu Y, Deisseroth A. Tumor vascular targeting therapy with viral vectors. Blood 107(8): 3027-33. (2006).
[40]
Hermida MA, Dinesh Kumar J, Leslie NR. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. Adv Biol Regul 65: 5-15. (2017).
[41]
Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104(6): 1433-9. (2008).
[42]
Lane-Donovan C, Herz J. ApoE, ApoE receptors, and the synapse in Alzheimer’s disease. Trends Endocrinol Metab 28(4): 273-84. (2017).
[43]
Zhao N, Liu CC, Van Ingelgom AJ, Martens YA, Linares C, Knight JA, et al. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes Neuron 96(1): 115-29 e5 (2017).
[44]
Zhao N, Liu CC, Qiao W, Bu G. Apolipoprotein E, receptors, and modulation of Alzheimer’s disease. Biol Psychiatry 83(4): 347-57. (2018).
[45]
Chen Y, Durakoglugil MS, Xian X, Herz J. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci USA 107(26): 12011-6. (2010).
[46]
Cash JG, Kuhel DG, Basford JE, Jaeschke A, Chatterjee TK, Weintraub NL, et al. Apolipoprotein E4 impairs macrophage efferocytosis and potentiates apoptosis by accelerating endoplasmic reticulum stress. J Biol Chem 287(33): 27876-84. (2012).
[47]
Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, et al. Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer’s disease brains at different stages of neurofibrillary degeneration. J Alzheimers Dis 3(1): 41-8. (2001).
[48]
Hoe HS, Pocivavsek A, Dai H, Chakraborty G, Harris DC, Rebeck GW. Effects of apoE on neuronal signaling and APP processing in rodent brain. Brain Res 1112(1): 70-9. (2006).
[49]
Lee KI, Su CC, Yang CY, Hung DZ, Lin CT, Lu TH, et al. Etoposide induces pancreatic beta-cells cytotoxicity via the
JNK/ERK/GSK-3 signaling-mediated mitochondria-dependent
apoptosis pathway. Toxicol In vitro: an international journal
published in association with BIBRA 36: 142-52 (2016).
[50]
Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9(1): 59-71. (2005).
[51]
Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease--is this type 3 diabetes? J Alzheimers Dis 7(1): 63-80. (2005).
[52]
Dose J, Huebbe P, Nebel A, Rimbach G. APOE genotype and stress response - a mini review. Lipids Health Dis 15: 121. (2016).
[53]
Dorey E, Bamji-Mirza M, Najem D, Li Y, Liu H, Callaghan D, et al. Apolipoprotein E isoforms differentially regulate alzheimer’s disease and amyloid-beta-induced inflammatory response in vivo and in vitro. J Alzheimers Dis 57(4): 1265-79. (2017).
[54]
Kusaka G, Ishikawa M, Nanda A, Granger DN, Zhang JH. Signaling pathways for early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab 24(8): 916-25. (2004).
[55]
Simpson JE, Ince PG, Shaw PJ, Heath PR, Raman R, Garwood CJ, et al. Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer’s pathology and APOE genotype. Neurobiol Aging 32(10): 1795-807. (2011).
[56]
Majewska E, Szeliga M. AKT/GSK3beta Signaling in Glioblastoma. Neurochem Res 42(3): 918-24. (2017).
[57]
Sun A, Liu M, Nguyen XV, Bing G. P38 MAP kinase is activated at early stages in Alzheimer’s disease brain. Exp Neurol 183(2): 394-405. (2003).
[58]
Lee JK, Kim NJ. Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer’s disease. Molecules 22(8) (2017).
[59]
Boehm-Cagan A, Bar R, Liraz O, Bielicki JK, Johansson JO, Michaelson DM. ABCA1 Agonist reverses the ApoE4-driven cognitive and brain pathologies. J Alzheimers Dis 54(3): 1219-33. (2016).
[60]
Luz I, Liraz O, Michaelson DM. An Anti-apoE4 specific monoclonal antibody counteracts the pathological effects of apoE4 in vivo. Curr Alzheimer Res 13(8): 918-29. (2016).
Related Books
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Frontiers in Clinical Drug Research-Dementia
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Article Metrics
49
3
1
1