Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease

Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1:507–537. https://doi.org/10.1146/annurev.genom.1.1.507 Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10(3):241–252. https://doi.org/10.1016/S1474-4422(10)70325-2 Theendakara V, Patent A, Peters Libeu CA, Philpot B, Flores S, Descamps O, Poksay KS, Zhang Q et al (2013) Neuroprotective Sirtuin ratio reversed by ApoE4. Proc Natl Acad Sci U S A 110(45):18303–18308. https://doi.org/10.1073/pnas.1314145110 Theendakara V, Peters-Libeu CA, Spilman P, Poksay KS, Bredesen DE, Rao RV (2016) Direct transcriptional effects of apolipoprotein E. J Neurosci 36(3):685–700. https://doi.org/10.1523/JNEUROSCI.3562-15.2016 Bredesen DE, Amos EC, Canick J, Ackerley M, Raji C, Fiala M, Ahdidan J (2016) Reversal of cognitive decline in Alzheimer’s disease. Aging (Albany NY) 8(6):1250–1258. 10.18632/aging.100981 Raichlen DA, Alexander GE (2014) Exercise, APOE genotype, and the evolution of the human lifespan. Trends Neurosci 37(5):247–255. https://doi.org/10.1016/j.tins.2014.03.001 Huang Y, Mahley RW (2014) Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis 72(Pt A):3–12. https://doi.org/10.1016/j.nbd.2014.08.025 Huang Y, Weisgraber KH, Mucke L, Mahley RW (2004) Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer’s disease. J Mol Neurosci 23(3):189–204. https://doi.org/10.1385/JMN:23:3:189 Grehan S, Tse E, Taylor JM (2001) Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain. J Neurosci 21(3):812–822 Ignatius MJ, Gebicke-Haerter PJ, Pitas RE, Shooter EM (1987) Apolipoprotein E in nerve injury and repair. Prog Brain Res 71:177–184 Pitas RE, Boyles JK, Lee SH, Foss D, Mahley RW (1987) Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta 917(1):148–161 Xu PT, Schmechel D, Qiu HL, Herbstreith M, Rothrock-Christian T, Eyster M, Roses AD, Gilbert JR (1999) Sialylated human apolipoprotein E (apoEs) is preferentially associated with neuron-enriched cultures from APOE transgenic mice. Neurobiol Dis 6(1):63–75. https://doi.org/10.1006/nbdi.1998.0213 Mahley RW, Weisgraber KH, Huang Y (2006) Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A 103(15):5644–5651. https://doi.org/10.1073/pnas.0600549103 Pfrieger FW (2003) Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol Life Sci 60(6):1158–1171. https://doi.org/10.1007/s00018-003-3018-7 Liao F, Yoon H, Kim J (2017) Apolipoprotein E metabolism and functions in brain and its role in Alzheimer’s disease. Curr Opin Lipidol 28(1):60–67. https://doi.org/10.1097/MOL.0000000000000383 Giau VV, Bagyinszky E, An SS, Kim SY (2015) Role of apolipoprotein E in neurodegenerative diseases. Neuropsychiatr Dis Treat 11:1723–1737. https://doi.org/10.2147/NDT.S84266 Helisalmi S, Linnaranta K, Lehtovirta M, Mannermaa A, Heinonen O, Ryynanen M, Riekkinen P Sr, Soininen H (1996) Apolipoprotein E polymorphism in patients with different neurodegenerative disorders. Neurosci Lett 205(1):61–64 Baum L, Lam LC, Kwok T, Lee J, Chiu HF, Mok VC, Wong A, Chen X et al (2006) Apolipoprotein E epsilon4 allele is associated with vascular dementia. Dement Geriatr Cogn Disord 22(4):301–305. https://doi.org/10.1159/000095246 Yin YW, Li JC, Wang JZ, Li BH, Pi Y, Yang QW, Fang CQ, Gao CY et al (2012) Association between apolipoprotein E gene polymorphism and the risk of vascular dementia: a meta-analysis. Neurosci Lett 514(1):6–11. https://doi.org/10.1016/j.neulet.2012.02.031 Chuang YF, Hayden KM, Norton MC, Tschanz J, Breitner JC, Welsh-Bohmer KA, Zandi PP (2010) Association between APOE epsilon4 allele and vascular dementia: The Cache County study. Dement Geriatr Cogn Disord 29(3):248–253. https://doi.org/10.1159/000285166 Stengard JH, Weiss KM, Sing CF (1998) An ecological study of association between coronary heart disease mortality rates in men and the relative frequencies of common allelic variations in the gene coding for apolipoprotein E. Hum Genet 103(2):234–241 Stengard JH, Pekkanen J, Sulkava R, Ehnholm C, Erkinjuntti T, Nissinen A (1995) Apolipoprotein E polymorphism, Alzheimer’s disease and vascular dementia among elderly Finnish men. Acta Neurol Scand 92(4):297–298 Stengard JH, Zerba KE, Pekkanen J, Ehnholm C, Nissinen A, Sing CF (1995) Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation 91(2):265–269 Lehtinen S, Lehtimaki T, Sisto T, Salenius JP, Nikkila M, Jokela H, Koivula T, Ebeling F et al (1995) Apolipoprotein E polymorphism, serum lipids, myocardial infarction and severity of angiographically verified coronary artery disease in men and women. Atherosclerosis 114(1):83–91 Eichner JE, Kuller LH, Orchard TJ, Grandits GA, McCallum LM, Ferrell RE, Neaton JD (1993) Relation of apolipoprotein E phenotype to myocardial infarction and mortality from coronary artery disease. Am J Cardiol 71(2):160–165 van der Walt A, Stankovich J, Bahlo M, Taylor BV, van der Mei IA, Foote SJ, Kilpatrick TJ, Rubio JP et al (2009) Apolipoprotein genotype does not influence MS severity, cognition, or brain atrophy. Neurology 73(13):1018–1025. https://doi.org/10.1212/WNL.0b013e3181b9c85e Lill CM, Liu T, Schjeide BM, Roehr JT, Akkad DA, Damotte V, Alcina A, Ortiz MA et al (2012) Closing the case of APOE in multiple sclerosis: no association with disease risk in over 29 000 subjects. J Med Genet 49(9):558–562. https://doi.org/10.1136/jmedgenet-2012-101175 Savettieri G, Messina D, Andreoli V, Bonavita S, Caltagirone C, Cittadella R, Farina D, Fazio MC et al (2004) Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis. J Neurol 251(10):1208–1214. https://doi.org/10.1007/s00415-004-0508-y Pinholt M, Frederiksen JL, Christiansen M (2006) The association between apolipoprotein E and multiple sclerosis. Eur J Neurol 13(6):573–580. https://doi.org/10.1111/j.1468-1331.2006.01360.x Shi J, Zhao CB, Vollmer TL, Tyry TM, Kuniyoshi SM (2008) APOE epsilon 4 allele is associated with cognitive impairment in patients with multiple sclerosis. Neurology 70(3):185–190. https://doi.org/10.1212/01.wnl.0000264004.62612.44 Koutsis G, Panas M, Giogkaraki E, Potagas C, Karadima G, Sfagos C, Vassilopoulos D (2007) APOE epsilon4 is associated with impaired verbal learning in patients with MS. Neurology 68(8):546–549. https://doi.org/10.1212/01.wnl.0000254468.51973.44 Ezquerra M, Campdelacreu J, Gaig C, Compta Y, Munoz E, Marti MJ, Valldeoriola F, Tolosa E (2008) Lack of association of APOE and tau polymorphisms with dementia in Parkinson’s disease. Neurosci Lett 448(1):20–23. https://doi.org/10.1016/j.neulet.2008.10.018 Ryu HG, Kwon OD (2010) Apolipoprotein E epsilon 4 allele is not associated with age at onset or MMSE of Parkinson’s disease in a Korean study. Parkinsonism Relat Disord 16(9):615–617. https://doi.org/10.1016/j.parkreldis.2010.06.015 Federoff M, Jimenez-Rolando B, Nalls MA, Singleton AB (2012) A large study reveals no association between APOE and Parkinson’s disease. Neurobiol Dis 46(2):389–392. https://doi.org/10.1016/j.nbd.2012.02.002 Harhangi BS, de Rijk MC, van Duijn CM, Van Broeckhoven C, Hofman A, Breteler MM (2000) APOE and the risk of PD with or without dementia in a population-based study. Neurology 54(6):1272–1276 Alzheimer’s Association (2015) Alzheimer’s disease Facts and Figures. Alzheimers Dement 11(3):332–384 Alzheimer’s Association (2017) Alzheimer’s disease Facts and Figures. Alzheimers Dement 13(4):325–373 Huang Y (2011) Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer’s disease: lessons from ApoE mouse models. Biochem Soc Trans 39(4):924–932. https://doi.org/10.1042/BST0390924 Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3):383–421 Finch CE, Morgan TE (2007) Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper. Curr Alzheimer Res 4(2):185–189 Bredesen DE (2009) Neurodegeneration in Alzheimer’s disease: caspases and synaptic element interdependence. Mol Neurodegener 4:27. https://doi.org/10.1186/1750-1326-4-27 Olsson A, Hoglund K, Sjogren M, Andreasen N, Minthon L, Lannfelt L, Buerger K, Moller HJ et al (2003) Measurement of alpha- and beta-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients. Exp Neurol 183(1):74–80 Cedazo-Minguez A, Wiehager B, Winblad B, Huttinger M, Cowburn RF (2001) Effects of apolipoprotein E (apoE) isoforms, beta-amyloid (Abeta) and apoE/Abeta complexes on protein kinase C-alpha (PKC-alpha) translocation and amyloid precursor protein (APP) processing in human SH-SY5Y neuroblastoma cells and fibroblasts. Neurochem Int 38(7):615–625 Vincent B, Smith JD (2001) Astrocytes down-regulate neuronal beta-amyloid precursor protein expression and modify its processing in an apolipoprotein E isoform-specific manner. Eur J Neurosci 14(2):256–266 Gonneaud J, Arenaza-Urquijo EM, Fouquet M, Perrotin A, Fradin S, de La Sayette V, Eustache F, Chetelat G (2016) Relative effect of APOE epsilon4 on neuroimaging biomarker changes across the lifespan. Neurology 87(16):1696–1703. https://doi.org/10.1212/WNL.0000000000003234 Kantarci K, Lowe V, Przybelski SA, Weigand SD, Senjem ML, Ivnik RJ, Preboske GM, Roberts R et al (2012) APOE modifies the association between Abeta load and cognition in cognitively normal older adults. Neurology 78(4):232–240. https://doi.org/10.1212/WNL.0b013e31824365ab Murphy KR, Landau SM, Choudhury KR, Hostage CA, Shpanskaya KS, Sair HI, Petrella JR, Wong TZ et al (2013) Mapping the effects of ApoE4, age and cognitive status on 18F-florbetapir PET measured regional cortical patterns of beta-amyloid density and growth. NeuroImage 78:474–480. https://doi.org/10.1016/j.neuroimage.2013.04.048 Huynh TV, Davis AA, Ulrich JD, Holtzman DM (2017) Apolipoprotein E and Alzheimer’s disease: the influence of apolipoprotein E on amyloid-beta and other amyloidogenic proteins. J Lipid Res 58(5):824–836. https://doi.org/10.1194/jlr.R075481 Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, Mintun MA (2010) APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 67(1):122–131. https://doi.org/10.1002/ana.21843 Tokuda T, Calero M, Matsubara E, Vidal R, Kumar A, Permanne B, Zlokovic B, Smith JD et al (2000) Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer’s amyloid beta peptides. Biochem J 348(Pt 2):359–365 Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV (2008) apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest 118(12):4002–4013. https://doi.org/10.1172/JCI36663 LaDu MJ, Falduto MT, Manelli AM, Reardon CA, Getz GS, Frail DE (1994) Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem 269(38):23403–23406 Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, Bu G, Frieden C et al (2013) ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci U S A 110(19):E1807–E1816. https://doi.org/10.1073/pnas.1220484110 Raber J, Wong D, Buttini M, Orth M, Bellosta S, Pitas RE, Mahley RW, Mucke L (1998) Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proc Natl Acad Sci U S A 95(18):10914–10919 Vitek MP, Brown CM, Colton CA (2009) APOE genotype-specific differences in the innate immune response. Neurobiol Aging 30(9):1350–1360. https://doi.org/10.1016/j.neurobiolaging.2007.11.014 Zhao L, Lin S, Bales KR, Gelfanova V, Koger D, Delong C, Hale J, Liu F et al (2009) Macrophage-mediated degradation of beta-amyloid via an apolipoprotein E isoform-dependent mechanism. J Neurosci 29(11):3603–3612. https://doi.org/10.1523/JNEUROSCI.5302-08.2009 Famenini S, Rigali EA, Olivera-Perez HM, Dang J, Chang MT, Halder R, Rao RV, Pellegrini M et al (2017) Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on omega-3 supplementation. FASEB J 31(1):148–160. https://doi.org/10.1096/fj.201600677RR Kanekiyo T, Bu G (2014) The low-density lipoprotein receptor-related protein 1 and amyloid-beta clearance in Alzheimer’s disease. Front Aging Neurosci 6:93. https://doi.org/10.3389/fnagi.2014.00093 Leissring MA (2008) The AbetaCs of Abeta-cleaving proteases. J Biol Chem 283(44):29645–29649. https://doi.org/10.1074/jbc.R800022200 Leissring MA (2016) Abeta-degrading proteases: therapeutic potential in Alzheimer disease. CNS Drugs 30(8):667–675. https://doi.org/10.1007/s40263-016-0364-1 Turner AJ, Nalivaeva NN (2007) New insights into the roles of metalloproteinases in neurodegeneration and neuroprotection. Int Rev Neurobiol 82:113–135. https://doi.org/10.1016/S0074-7742(07)82006-X Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, Gerard C, Hama E et al (2001) Metabolic regulation of brain Abeta by neprilysin. Science 292(5521):1550–1552. https://doi.org/10.1126/science.1059946 Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, Schellenberg GD, Jin LW et al (2003) Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol 162(1):313–319 Du J, Chang J, Guo S, Zhang Q, Wang Z (2009) ApoE 4 reduces the expression of Abeta degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons. Neurosci Lett 464(2):140–145. https://doi.org/10.1016/j.neulet.2009.07.032 Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B et al (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58(5):681–693. https://doi.org/10.1016/j.neuron.2008.04.010 Li J, Kanekiyo T, Shinohara M, Zhang Y, LaDu MJ, Xu H, Bu G (2012) Differential regulation of amyloid-beta endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. J Biol Chem 287(53):44593–44601. https://doi.org/10.1074/jbc.M112.420224 Tai LM, Youmans KL, Jungbauer L, Yu C, Ladu MJ (2011) Introducing human APOE into Abeta transgenic mouse models. Int J Alzheimers Dis 2011:810981. https://doi.org/10.4061/2011/810981 Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, Xu Q, Dee Fish J, Wyss-Coray T et al (2004) Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci 24(10):2527–2534. https://doi.org/10.1523/JNEUROSCI.4315-03.2004 Buttini M, Akeefe H, Lin C, Mahley RW, Pitas RE, Wyss-Coray T, Mucke L (2000) Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease. Neuroscience 97(2):207–210 Buttini M, Orth M, Bellosta S, Akeefe H, Pitas RE, Wyss-Coray T, Mucke L, Mahley RW (1999) Expression of human apolipoprotein E3 or E4 in the brains of Apoe−/− mice: isoform-specific effects on neurodegeneration. J Neurosci 19(12):4867–4880 Harris FM, Brecht WJ, Xu Q, Tesseur I, Kekonius L, Wyss-Coray T, Fish JD, Masliah E et al (2003) Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci U S A 100(19):10966–10971. https://doi.org/10.1073/pnas.1434398100 Huang Y, Liu XQ, Wyss-Coray T, Brecht WJ, Sanan DA, Mahley RW (2001) Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci U S A 98(15):8838–8843. https://doi.org/10.1073/pnas.151254698 Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, Zwilling D, Yan TX et al (2010) Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci 30(41):13707–13717. https://doi.org/10.1523/JNEUROSCI.4040-10.2010 Andrews-Zwilling Y, Gillespie AK, Kravitz AV, Nelson AB, Devidze N, Lo I, Yoon SY, Bien-Ly N et al (2012) Hilar GABAergic interneuron activity controls spatial learning and memory retrieval. PLoS One 7(7):e40555. https://doi.org/10.1371/journal.pone.0040555 Tesseur I, Van Dorpe J, Spittaels K, Van den Haute C, Moechars D, Van Leuven F (2000) Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am J Pathol 156(3):951–964. https://doi.org/10.1016/S0002-9440(10)64963-2 Tesseur I, Van Dorpe J, Bruynseels K, Bronfman F, Sciot R, Van Lommel A, Van Leuven F (2000) Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am J Pathol 157(5):1495–1510. https://doi.org/10.1016/S0002-9440(10)64788-8 Sullivan PM, Han B, Liu F, Mace BE, Ervin JF, Wu S, Koger D, Paul S et al (2011) Reduced levels of human apoE4 protein in an animal model of cognitive impairment. Neurobiol Aging 32(5):791–801. https://doi.org/10.1016/j.neurobiolaging.2009.05.011 Bour A, Grootendorst J, Vogel E, Kelche C, Dodart JC, Bales K, Moreau PH, Sullivan PM et al (2008) Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks. Behav Brain Res 193(2):174–182. https://doi.org/10.1016/j.bbr.2008.05.008 Dumanis SB, Tesoriero JA, Babus LW, Nguyen MT, Trotter JH, Ladu MJ, Weeber EJ, Turner RS et al (2009) ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J Neurosci 29(48):15317–15322. https://doi.org/10.1523/JNEUROSCI.4026-09.2009 Grootendorst J, Bour A, Vogel E, Kelche C, Sullivan PM, Dodart JC, Bales K, Mathis C (2005) Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior. Behav Brain Res 159(1):1–14. https://doi.org/10.1016/j.bbr.2004.09.019 Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J et al (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 97(6):2892–2897. https://doi.org/10.1073/pnas.050004797 Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM, Bales K, Ashe KH et al (2000) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol 47(6):739–747 Ji Y, Gong Y, Gan W, Beach T, Holtzman DM, Wisniewski T (2003) Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer’s disease patients. Neuroscience 122(2):305–315 Li G, Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Ring K, Halabisky B, Deng C et al (2009) GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell 5(6):634–645. https://doi.org/10.1016/j.stem.2009.10.015 Lattanzio F, Carboni L, Carretta D, Rimondini R, Candeletti S, Romualdi P (2014) Human apolipoprotein E4 modulates the expression of Pin1, Sirtuin 1, and Presenilin 1 in brain regions of targeted replacement apoE mice. Neuroscience 256:360–369. https://doi.org/10.1016/j.neuroscience.2013.10.017 Kumar R, Chaterjee P, Sharma PK, Singh AK, Gupta A, Gill K, Tripathi M, Dey AB et al (2013) Sirtuin1: a promising serum protein marker for early detection of Alzheimer’s disease. PLoS One 8(4):e61560. https://doi.org/10.1371/journal.pone.0061560 Lee HR, Shin HK, Park SY, Kim HY, Lee WS, Rhim BY, Hong KW, Kim CD (2014) Cilostazol suppresses beta-amyloid production by activating a disintegrin and metalloproteinase 10 via the upregulation of SIRT1-coupled retinoic acid receptor-beta. J Neurosci Res 92(11):1581–1590. https://doi.org/10.1002/jnr.23421 Herskovits AZ, Guarente L (2014) SIRT1 in neurodevelopment and brain senescence. Neuron 81(3):471–483. https://doi.org/10.1016/j.neuron.2014.01.028 Porquet D, Casadesus G, Bayod S, Vicente A, Canudas AM, Vilaplana J, Pelegri C, Sanfeliu C et al (2013) Dietary resveratrol prevents Alzheimer’s markers and increases life span in SAMP8. Age 35(5):1851–1865. https://doi.org/10.1007/s11357-012-9489-4 Rege SD, Geetha T, Griffin GD, Broderick TL, Babu JR (2014) Neuroprotective effects of resveratrol in Alzheimer disease pathology. Front Aging Neurosci 6:218. https://doi.org/10.3389/fnagi.2014.00218 Hubbard BP, Sinclair DA (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 35(3):146–154. https://doi.org/10.1016/j.tips.2013.12.004 Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y et al (2010) Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67(6):953–966. https://doi.org/10.1016/j.neuron.2010.08.044 Sen A, Nelson TJ, Alkon DL (2015) ApoE4 and Abeta oligomers reduce BDNF expression via HDAC nuclear translocation. J Neurosci 35(19):7538–7551. https://doi.org/10.1523/JNEUROSCI.0260-15.2015 Huang YA, Zhou B, Wernig M, Sudhof TC (2017) ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Abeta secretion. Cell 168(3):427–441 e421. https://doi.org/10.1016/j.cell.2016.12.044 Simpson JE, Ince PG, Shaw PJ, Heath PR, Raman R, Garwood CJ, Gelsthorpe C, Baxter L et al (2011) Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer’s pathology and APOE genotype. Neurobiol Aging 32(10):1795–1807. https://doi.org/10.1016/j.neurobiolaging.2011.04.013 Urfer-Buchwalder A, Urfer R (2017) Identification of a nuclear respiratory factor 1 recognition motif in the apolipoprotein E variant APOE4 linked to Alzheimer’s disease. Sci Rep 7:40668. https://doi.org/10.1038/srep40668 Zhang G, Curtiss LK, Wade RL, Dyer CA (1998) An apolipoprotein E synthetic peptide selectively modulates the transcription of the gene for rat ovarian theca and interstitial cell P450 17alpha-hydroxylase, C17-20 lyase. J Lipid Res 39(12):2406–2414 Levros LC Jr, Labrie M, Charfi C, Rassart E (2013) Binding and repressive activities of apolipoprotein E3 and E4 isoforms on the human ApoD promoter. Mol Neurobiol 48(3):669–680. https://doi.org/10.1007/s12035-013-8456-0 Theendakara V, Bredesen DE, Rao RV (2017) Downregulation of protein phosphatase 2A by apolipoprotein E: implications for Alzheimer’s disease. Mol Cell Neurosci. https://doi.org/10.1016/j.mcn.2017.07.002 Del Villar K, Miller CA (2004) Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer’s disease brain and hippocampal neurons. Proc Natl Acad Sci U S A 101(12):4210–4215. https://doi.org/10.1073/pnas.0307349101 Quintana FJ, Zaltzman R, Fernandez-Montesinos R, Herrera JL, Gozes I, Cohen IR, Pozo D (2006) NAP, a peptide derived from the activity-dependent neuroprotective protein, modulates macrophage function. Ann N Y Acad Sci 1070:500–506. https://doi.org/10.1196/annals.1317.069 de Bie P, van de Sluis B, Burstein E, Duran KJ, Berger R, Duckett CS, Wijmenga C, Klomp LW (2006) Characterization of COMMD protein-protein interactions in NF-kappaB signalling. Biochem J 398(1):63–71. https://doi.org/10.1042/BJ20051664 Fernandez-Montesinos R, Torres M, Baglietto-Vargas D, Gutierrez A, Gozes I, Vitorica J, Pozo D (2010) Activity-dependent neuroprotective protein (ADNP) expression in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer’s disease. J Mol Neurosci 41(1):114–120. https://doi.org/10.1007/s12031-009-9300-x Janssens V, Longin S, Goris J (2008) PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci 33(3):113–121. https://doi.org/10.1016/j.tibs.2007.12.004 Torrent L, Ferrer I (2012) PP2A and Alzheimer disease. Curr Alzheimer Res 9(2):248–256 Sontag JM, Sontag E (2014) Protein phosphatase 2A dysfunction in Alzheimer’s disease. Front Mol Neurosci 7:16. https://doi.org/10.3389/fnmol.2014.00016 Martin L, Latypova X, Wilson CM, Magnaudeix A, Perrin ML, Terro F (2013) Tau protein phosphatases in Alzheimer’s disease: the leading role of PP2A. Ageing Res Rev 12(1):39–49. https://doi.org/10.1016/j.arr.2012.06.008 Iqbal K, Liu F, Gong CX (2016) Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 12(1):15–27. https://doi.org/10.1038/nrneurol.2015.225 Sommer LM, Cho H, Choudhary M, Seeling JM (2015) Evolutionary analysis of the B56 gene family of PP2A regulatory subunits. Int J Mol Sci 16(5):10134–10157. https://doi.org/10.3390/ijms160510134 Sangodkar J, Farrington CC, McClinch K, Galsky MD, Kastrinsky DB, Narla G (2016) All roads lead to PP2A: exploiting the therapeutic potential of this phosphatase. FEBS J 283(6):1004–1024. https://doi.org/10.1111/febs.13573 Vogelsberg-Ragaglia V, Schuck T, Trojanowski JQ, Lee VM (2001) PP2A mRNA expression is quantitatively decreased in Alzheimer’s disease hippocampus. Exp Neurol 168(2):402–412. https://doi.org/10.1006/exnr.2001.7630 Sontag E, Luangpirom A, Hladik C, Mudrak I, Ogris E, Speciale S, White CL 3rd (2004) Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol 63(4):287–301 Braithwaite SP, Stock JB, Lombroso PJ, Nairn AC (2012) Protein phosphatases and Alzheimer’s disease. Prog Mol Biol Transl Sci 106:343–379. https://doi.org/10.1016/B978-0-12-396456-4.00012-2 Zhong N, Ramaswamy G, Weisgraber KH (2009) Apolipoprotein E4 domain interaction induces endoplasmic reticulum stress and impairs astrocyte function. J Biol Chem 284(40):27273–27280. https://doi.org/10.1074/jbc.M109.014464 Cash JG, Kuhel DG, Basford JE, Jaeschke A, Chatterjee TK, Weintraub NL, Hui DY (2012) Apolipoprotein E4 impairs macrophage efferocytosis and potentiates apoptosis by accelerating endoplasmic reticulum stress. J Biol Chem 287(33):27876–27884. https://doi.org/10.1074/jbc.M112.377549 Rao RV, Bredesen DE (2004) Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr Opin Cell Biol 16(6):653–662 Drori A, Misaghi S, Haimovich J, Messerle M, Tirosh B (2010) Prolonged endoplasmic reticulum stress promotes mislocalization of immunoglobulins to the cytoplasm. Mol Immunol 47(9):1719–1727. https://doi.org/10.1016/j.molimm.2010.03.006 Miesbauer M, Rambold AS, Winklhofer KF, Tatzelt J (2010) Targeting of the prion protein to the cytosol: mechanisms and consequences. Curr Issues Mol Biol 12(2):109–118 Quinn CM, Kagedal K, Terman A, Stroikin U, Brunk UT, Jessup W, Garner B (2004) Induction of fibroblast apolipoprotein E expression during apoptosis, starvation-induced growth arrest and mitosis. Biochem J 378(Pt 3):753–761. https://doi.org/10.1042/BJ20031352 Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA (2000) Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer’s disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol 157(1):277–286 Ji ZS, Miranda RD, Newhouse YM, Weisgraber KH, Huang Y, Mahley RW (2002) Apolipoprotein E4 potentiates amyloid beta peptide-induced lysosomal leakage and apoptosis in neuronal cells. J Biol Chem 277(24):21821–21828. https://doi.org/10.1074/jbc.M112109200 Flavin WP, Bousset L, Green ZC, Chu Y, Skarpathiotis S, Chaney MJ, Kordower JH, Melki R et al (2017) Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins. Acta Neuropathol. https://doi.org/10.1007/s00401-017-1722-x Zerbinatti CV, Wahrle SE, Kim H, Cam JA, Bales K, Paul SM, Holtzman DM, Bu G (2006) Apolipoprotein E and low density lipoprotein receptor-related protein facilitate intraneuronal Abeta42 accumulation in amyloid model mice. J Biol Chem 281(47):36180–36186. https://doi.org/10.1074/jbc.M604436200 Hu X, Crick SL, Bu G, Frieden C, Pappu RV, Lee JM (2009) Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide. Proc Natl Acad Sci U S A 106(48):20324–20329. https://doi.org/10.1073/pnas.0911281106 Lee CY, Tse W, Smith JD, Landreth GE (2012) Apolipoprotein E promotes beta-amyloid trafficking and degradation by modulating microglial cholesterol levels. J Biol Chem 287(3):2032–2044. https://doi.org/10.1074/jbc.M111.295451 Kim WS, Elliott DA, Kockx M, Kritharides L, Rye KA, Jans DA, Garner B (2008) Analysis of apolipoprotein E nuclear localization using green fluorescent protein and biotinylation approaches. Biochem J 409(3):701–709. https://doi.org/10.1042/BJ20071261 Rohn TT (2013) Proteolytic cleavage of apolipoprotein E4 as the keystone for the heightened risk associated with Alzheimer’s disease. Int J Mol Sci 14(7):14908–14922. https://doi.org/10.3390/ijms140714908 Love JE, Day RJ, Gause JW, Brown RJ, Pu X, Theis DI, Caraway CA, Poon WW et al (2017) Nuclear uptake of an amino-terminal fragment of apolipoprotein E4 promotes cell death and localizes within microglia of the Alzheimer’s disease brain. Int J Physiol Pathophysiol Pharmacol 9(2):40–57 Fazio S, Linton MF, Swift LL (2000) The cell biology and physiologic relevance of ApoE recycling. Trends Cardiovasc Med 10(1):23–30 Semenkovich CF, Ostlund RE Jr, Olson MO, Yang JW (1990) A protein partially expressed on the surface of HepG2 cells that binds lipoproteins specifically is nucleolin. Biochemistry 29(41):9708–9713 Said EA, Krust B, Nisole S, Svab J, Briand JP, Hovanessian AG (2002) The anti-HIV cytokine midkine binds the cell surface-expressed nucleolin as a low affinity receptor. J Biol Chem 277(40):37492–37502. https://doi.org/10.1074/jbc.M201194200 Shibata Y, Muramatsu T, Hirai M, Inui T, Kimura T, Saito H, McCormick LM, Bu G et al (2002) Nuclear targeting by the growth factor midkine. Mol Cell Biol 22(19):6788–6796 Panin LE, Russkikh GS, Polyakov LM (2000) Detection of apolipoprotein A-I, B, and E immunoreactivity in the nuclei of various rat tissue cells. Biochemistry (Mosc) 65(12):1419–1423 Chen YC, Pohl G, Wang TL, Morin PJ, Risberg B, Kristensen GB, Yu A, Davidson B et al (2005) Apolipoprotein E is required for cell proliferation and survival in ovarian cancer. Cancer Res 65(1):331–337 Wang M, Kaufman RJ (2014) The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer 14(9):581–597. https://doi.org/10.1038/nrc3800 Venanzoni MC, Giunta S, Muraro GB, Storari L, Crescini C, Mazzucchelli R, Montironi R, Seth A (2003) Apolipoprotein E expression in localized prostate cancers. Int J Oncol 22(4):779–786 Majka J, Speck C (2007) Analysis of protein-DNA interactions using surface plasmon resonance. Adv Biochem Eng Biotechnol 104:13–36 Jantz D, Berg JM (2010) Probing the DNA-binding affinity and specificity of designed zinc finger proteins. Biophys J 98(5):852–860. https://doi.org/10.1016/j.bpj.2009.11.021 Rohs R, West SM, Sosinsky A, Liu P, Mann RS, Honig B (2009) The role of DNA shape in protein-DNA recognition. Nature 461(7268):1248–1253. https://doi.org/10.1038/nature08473 Luscombe NM, Laskowski RA, Thornton JM (2001) Amino acid-base interactions: a three-dimensional analysis of protein-DNA interactions at an atomic level. Nucleic Acids Res 29(13):2860–2874 Rohs R, Jin X, West SM, Joshi R, Honig B, Mann RS (2010) Origins of specificity in protein-DNA recognition. Annu Rev Biochem 79:233–269. https://doi.org/10.1146/annurev-biochem-060408-091030 Danielsson B, Ekman R, Johansson BG, Nilsson-Ehle P, Petersson BG (1978) Isolation of a high density lipoprotein with high contents of arginine-rich apoprotein (apoE) from rat plasma. FEBS Lett 86(2):299–302 Jaeger S, Pietrzik CU (2008) Functional role of lipoprotein receptors in Alzheimer’s disease. Curr Alzheimer Res 5(1):15–25