Ethanol Alters APP Processing and Aggravates Alzheimer-Associated Phenotypes

Molecular Neurobiology - Tập 55 - Trang 5006-5018 - 2017
Daochao Huang1, Mengjiao Yu1, Shou Yang1, Dandan Lou1, Weitao Zhou1, Lingling Zheng1, Zhe Wang2, Fang Cai2, Weihui Zhou1, Tingyu Li1, Weihong Song1,2
1Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
2Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, Canada

Tóm tắt

The majority of Alzheimer’s disease (AD) cases are sporadic with unknown causes. Many dietary factors including excessive alcohol intake have been reported to increase the risk to develop AD. The effect of alcohol on cognitive functions and AD pathogenesis remains elusive. In this study, we investigated the relationship between ethanol exposure and Alzheimer’s disease. Cell cultures were treated with ethanol at different dosages for different durations up to 48 h and an AD model mouse was fed with ethanol for 4 weeks. We found that ethanol treatment altered amyloid β precursor protein (APP) processing in cells and transgenic AD model mice. High ethanol exposure increased the levels of APP and beta-site APP cleaving enzyme 1 (BACE1) and significantly promoted amyloid β protein (Aβ) production both in vitro and in vivo. The upregulated APP and BACE1 expressions upon ethanol treatment were at least partially due to the activation of APP and BACE1 transcriptions. Furthermore, ethanol treatment increased the deposition of Aβ and neuritic plaque formation in the brains and exuberated learning and memory impairments in transgenic AD model mice. Taken together, our results demonstrate that excessive ethanol intake facilitates AD pathogenesis.

Tài liệu tham khảo

Glenner GG, Wong CW (1984) Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122(3):1131–1135 Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120(3):885–890 Zhang X, Song W (2013) The role of APP and BACE1 trafficking in APP processing and amyloid-beta generation. Alzheimers Res Ther 5(5):46 Sun XB-BK, Song W (2012) Regulation of β-site APP-cleaving enzyme 1 gene expression and its role in Alzheimer’s disease. J Neurochem 120(Suppl 1):62–70 Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF et al (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402(6761):537–540 Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S et al (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286(5440):735–741 Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC et al (1999) Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 402(6761):533–537 Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE et al (1999) Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 14(6):419–427 Deng Y, Wang Z, Wang R, Zhang X, Zhang S, Wu Y, Staufenbiel M, Cai F et al (2013) Amyloid-beta protein (Abeta) Glu11 is the major beta-secretase site of beta-site amyloid-beta precursor protein-cleaving enzyme 1 (BACE1), and shifting the cleavage site to Abeta Asp1 contributes to Alzheimer pathogenesis. Eur J Neurosci 37(12):1962–1969 Sun X, He G, Song W (2006) BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer’s disease in Down syndrome. FASEB J 20(9):1369–1376 Sun X, Wang Y, Qing H, Christensen MA, Liu Y, Zhou W, Tong Y, Xiao C et al (2005) Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB J 19(7):739–749 Yang Y, Wu Y, Zhang S, Song W (2013) High glucose promotes Abeta production by inhibiting APP degradation. PLoS One 8(7):e69824 Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y et al (2013) Inhibition of GSK3beta-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest 123(1):224–235 Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S et al (2008) Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models. J Exp Med 205(12):2781–2789 Zeng J, Chen L, Wang Z, Chen Q, Fan Z, Jiang H, Wu Y, Ren L et al (2017) Marginal vitamin A deficiency facilitates Alzheimer’s pathogenesis. Acta Neuropathol 133(6):967–982 Zhang S, Wang Z, Cai F, Zhang M, Wu Y, Zhang J, Song W (2017) BACE1 cleavage site selection critical for amyloidogenesis and Alzheimer’s pathogenesis. J Neurosci 37(29):6915–6925 Reitz C, Mayeux R (2014) Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88(4):640–651 Ramesh BN, Rao TS, Prakasam A, Sambamurti K, Rao KS (2010) Neuronutrition and Alzheimer’s disease. J Alzheimers Dis 19(4):1123–1139 Piazza-Gardner AK, Gaffud TJ, Barry AE (2013) The impact of alcohol on Alzheimer’s disease: a systematic review. Aging Ment Health 17(2):133–146 Harwood DG, Kalechstein A, Barker WW, Strauman S, St George-Hyslop P, Iglesias C, Loewenstein D, Duara R (2010) The effect of alcohol and tobacco consumption, and apolipoprotein E genotype, on the age of onset in Alzheimer’s disease. Int J Geriatr Psychiatry 25(5):511–518 Wang J, Ho L, Zhao Z, Seror I, Humala N, Dickstein DL, Thiyagarajan M, Percival SS et al (2006) Moderate consumption of Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer’s disease. FASEB J 20(13):2313–2320 Deng J, Zhou DH, Li J, Wang YJ, Gao C, Chen M (2006) A 2-year follow-up study of alcohol consumption and risk of dementia. Clin Neurol Neurosurg 108(4):378–383 Weyerer S, Schaufele M, Wiese B, Maier W, Tebarth F, van den Bussche H, Pentzek M, Bickel H et al (2011) Current alcohol consumption and its relationship to incident dementia: results from a 3-year follow-up study among primary care attenders aged 75 years and older. Age Ageing 40(4):456–463 Guizzetti M, Costa LG (2007) Cholesterol homeostasis in the developing brain: a possible new target for ethanol. Hum Exp Toxicol 26(4):355–360 Arendt T (1994) Impairment in memory function and neurodegenerative changes in the cholinergic basal forebrain system induced by chronic intake of ethanol. J Neural Transm Suppl 44:173–187 Ehrlich D, Pirchl M, Humpel C (2012) Effects of long-term moderate ethanol and cholesterol on cognition, cholinergic neurons, inflammation, and vascular impairment in rats. Neuroscience 205:154–166 Kim SR, Jeong HY, Yang S, Choi SP, Seo MY, Yun YK, Choi Y, Baik SH et al (2011) Effects of chronic alcohol consumption on expression levels of APP and Abeta-producing enzymes. BMB Rep 44(2):135–139 Gil-Mohapel J, Boehme F, Kainer L, Christie BR (2010) Hippocampal cell loss and neurogenesis after fetal alcohol exposure: insights from different rodent models. Brain Res Rev 64(2):283–303 Lahiri DK, Nall C, Chen D, Zaphiriou M, Morgan C, Nurnberger JI Sr (2002) Developmental expression of the beta-amyloid precursor protein and heat-shock protein 70 in the cerebral hemisphere region of the rat brain. Ann N Y Acad Sci 965:324–333 Aho L, Karkola K, Juusela J, Alafuzoff I (2009) Heavy alcohol consumption and neuropathological lesions: a post-mortem human study. J Neurosci Res 87(12):2786–2792 Dong Z, Han H, Li H, Bai Y, Wang W, Tu M, Peng Y, Zhou L et al (2015) Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis. J Clin Invest 125(1):234–247 Thiele TE, Navarro M (2014) “Drinking in the dark” (DID) procedures: a model of binge-like ethanol drinking in non-dependent mice. Alcohol 48(3):235–241 Rhodes JS, Best K, Belknap JK, Finn DA, Crabbe JC (2005) Evaluation of a simple model of ethanol drinking to intoxication in C57BL/6J mice. Physiol Behav 84(1):53–63 Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE et al (2006) Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A 103(49):18727–18732 Bromley-Brits K, Deng Y, Song W (2011) Morris water maze test for learning and memory deficits in Alzheimer’s disease model mice. J Vis Exp 53:e2920 Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA (2000) Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat Cell Biol 2(7):463–465 Christensen MA, Zhou W, Qing H, Lehman A, Philipsen S, Song W (2004) Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1. Mol Cell Biol 24(2):865–874 Santhakumar V, Wallner M, Otis TS (2007) Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition. Alcohol 41(3):211–221 Moykkynen T, Korpi ER (2012) Acute effects of ethanol on glutamate receptors. Basic Clin Pharmacol Toxicol 111(1):4–13 Harwood DG, Barker WW, Loewenstein DA, Ownby RL, St George-Hyslop P, Mullan M, Duara R (1999) A cross-ethnic analysis of risk factors for AD in white Hispanics and white non-Hispanics. Neurology 52(3):551–556 Wheeler MD, Kono H, Rusyn I, Arteel GE, McCarty D, Samulski RJ, Thurman RG (2000) Chronic ethanol increases adeno-associated viral transgene expression in rat liver via oxidant and NFkappaB-dependent mechanisms. Hepatology 32(5):1050–1059 Yao Z, Zhang J, Dai J, Keller ET (2001) Ethanol activates NFkappaB DNA binding and p56lck protein tyrosine kinase in human osteoblast-like cells. Bone 28(2):167–173 Ward RJ, Zhang Y, Crichton RR, Piret B, Piette J, de Witte P (1996) Identification of the nuclear transcription factor NFkappaB in rat after in vivo ethanol administration. FEBS Lett 389(2):119–122 Magne L, Blanc E, Legrand B, Lucas D, Barouki R, Rouach H, Garlatti M (2011) ATF4 and the integrated stress response are induced by ethanol and cytochrome P450 2E1 in human hepatocytes. J Hepatol 54(4):729–737 Buggia-Prevot V, Sevalle J, Rossner S, Checler F (2008) NFkappaB-dependent control of BACE1 promoter transactivation by Abeta42. J Biol Chem 283(15):10037–10047 Chen CH, Zhou W, Liu S, Deng Y, Cai F, Tone M, Tone Y, Tong Y et al (2012) Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. Int J Neuropsychopharmacol 15(1):77–90 Walton JR, Wang MX (2009) APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer’s disease. J Inorg Biochem 103(11):1548–1554 Barkley-Levenson AM, Crabbe JC (2012) Ethanol drinking microstructure of a high drinking in the dark selected mouse line. Alcohol Clin Exp Res 36(8):1330–1339 Criado JR, Liu T, Ehlers CL, Mathe AA (2011) Prolonged chronic ethanol exposure alters neuropeptide Y and corticotropin-releasing factor levels in the brain of adult Wistar rats. Pharmacol Biochem Behav 99(1):104–111 Pandey SC, Ugale R, Zhang H, Tang L, Prakash A (2008) Brain chromatin remodeling: a novel mechanism of alcoholism. J Neurosci 28(14):3729–3737 Piano MR, Carrigan TM, Schwertz DW (2005) Sex differences in ethanol liquid diet consumption in Sprague-Dawley rats. Alcohol 35(2):113–118 Hanson GR, Li TK (2003) Public health implications of excessive alcohol consumption. JAMA 289(8):1031–1032 Fernandez GM, Lew BJ, Vedder LC, Savage LM (2017) Chronic intermittent ethanol exposure leads to alterations in brain-derived neurotrophic factor within the frontal cortex and impaired behavioral flexibility in both adolescent and adult rats. Neuroscience 348:324–334 Cash C, Peacock A, Barrington H, Sinnett N, Bruno R (2015) Detecting impairment: sensitive cognitive measures of dose-related acute alcohol intoxication. J Psychopharmacol 29(4):436–446 Brust JC (2010) Ethanol and cognition: indirect effects, neurotoxicity and neuroprotection: a review. Int J Environ Res Public Health 7(4):1540–1557 Crabbe JC, Harris RA, Koob GF (2011) Preclinical studies of alcohol binge drinking. Ann N Y Acad Sci 1216:24–40 Crews FT, Nixon K (2009) Mechanisms of neurodegeneration and regeneration in alcoholism. Alcohol Alcohol 44(2):115–127 Allen-Gipson DS, Jarrell JC, Bailey KL, Robinson JE, Kharbanda KK, Sisson JH, Wyatt TA (2009) Ethanol blocks adenosine uptake via inhibiting the nucleoside transport system in bronchial epithelial cells. Alcohol Clin Exp Res 33(5):791–798 Deng XS, Deitrich RA (2007) Ethanol metabolism and effects: nitric oxide and its interaction. Curr Clin Pharmacol 2(2):145–153 Jamal M, Ameno K, Miki T, Wang W, Kumihashi M, Isse T, Kawamoto T, Kitagawa K et al (2009) Cholinergic alterations following alcohol exposure in the frontal cortex of Aldh2-deficient mice models. Brain Res 1295:37–43 McKinney M, Jacksonville MC (2005) Brain cholinergic vulnerability: relevance to behavior and disease. Biochem Pharmacol 70(8):1115–1124 Abreu-Villaca Y, de Carvalho Graca AC, Ribeiro-Carvalho A, Naiff Vde F, Manhaes AC, Filgueiras CC (2013) Combined exposure to tobacco smoke and ethanol in adolescent mice elicits memory and learning deficits both during exposure and withdrawal. Nicotine Tob Res 15(7):1211–1221 Vaglenova J, Pandiella N, Wijayawardhane N, Vaithianathan T, Birru S, Breese C, Suppiramaniam V, Randal C (2008) Aniracetam reversed learning and memory deficits following prenatal ethanol exposure by modulating functions of synaptic AMPA receptors. Neuropsychopharmacology 33(5):1071–1083