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Current Alzheimer Research

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

The Role of MAPK's Signaling in Mediating ApoE4-Driven Pathology In Vivo

Author(s): Shiran Salomon-Zimri, Amit Koren, Ariel Angel, Tali Ben-Zur, Daniel Offen and Daniel M. Michaelson*

Volume 16, Issue 4, 2019

Page: [281 - 292] Pages: 12

DOI: 10.2174/1567205016666190228120254

Price: $65

Abstract

Background: Alzheimer's Disease (AD) is associated with impairments in key brain Mitogen- Activated Protein Kinase (MAPK) signaling cascades including the p38, c-Jun N-terminal kinase (JNK), ERK and Akt pathways. Apolipoprotein E4 (ApoE4) is the most prevalent genetic risk factor of AD.

Objectives: To investigate the extent to which the MAPK signaling pathway plays a role in mediating the pathological effects of apoE4 and can be reversed by experimental manipulations.

Methods: Measurements of total level and activation of MAPK signaling pathway factors, obtained utilizing immunoblot assay of hippocampal tissues from naïve and viral-treated apoE3 and apoE4 targeted replacement mice.

Results: ApoE4 mice showed robust activation of the stress related p38 and JNK pathways and a corresponding decrease in Akt activity, which is coupled to activation of GSK3β and tau hyperphosphorylation. There was no effect on the ERK pathway. We have previously shown that the apoE4- related pathology, namely; accumulation of Aβ, hyper-phosphorylated tau, synaptic impairments and decreased VEGF levels can be reversed by up-regulation of VEGF level utilizing a VEGF-expressing adeno-associated virus. Utilizing this approach, we assessed the extent to which the AD-hallmark and synaptic pathologies of apoE4 are related to the corresponding MAPK signaling effects. This revealed that the reversal of the apoE4-driven pathology via VEGF treatment was associated with a reversal of the p38 and Akt related effects.

Conclusion: Taken together, these results suggest that the p38 and Akt pathways play a role in mediating the AD-related pathological effects of apoE4 in the hippocampus.

Keywords: Alzheimer's disease (AD), apolipoprotein E4 (apoE4), VEGF, MAPK, signaling, adeno-associated virus, hippocampus, targeted replacement mice.

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[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).
[61]
Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron 63(3): 287-303. (2009).
[62]
Sun GZ, He YC, Ma XK, Li ST, Chen DJ, Gao M, et al. Hippocampal synaptic and neural network deficits in young mice carrying the human APOE4 gene. CNS Neurosci Ther 23(9): 748-58. (2017).

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