APOE and Alzheimer’s Disease: Evidence Mounts that Targeting APOE4 may Combat Alzheimer’s Pathogenesis

Abstract

Alzheimer’s disease (AD) is an immutable neurodegenerative disease featured by the two hallmark brain pathologies that are the extracellular amyloid ß (Aß) and intraneuronal tau protein. People carrying the APOE4 allele are at high risk of AD concerning the ones carrying the ε3 allele, while the ε2 allele abates risk. ApoE isoforms exert a central role in controlling the transport of brain lipid, neuronal signaling, mitochondrial function, glucose metabolism, and neuroinflammation. Regardless of widespread indispensable studies, the appropriate function of APOE in AD etiology stays ambiguous. Existing proof recommends that the disparate outcomes of ApoE isoforms on Aβ accretion and clearance have a distinct function in AD pathogenesis. ApoE–lipoproteins combine diverse cell-surface receptors to transport lipids and moreover to lipophilic Aβ peptide, that is believed to begin deadly events that generate neurodegeneration in the AD. ApoE has great influence in tau pathogenesis, tau-mediated neurodegeneration, and neuroinflammation, as well as α-synucleinopathy, lipid metabolism, and synaptic plasticity despite the presence of Aβ pathology. ApoE4 shows the deleterious effect for AD while the lack of ApoE4 is defensive. Therapeutic strategies primarily depend on APOE suggest to lessen the noxious effects of ApoE4 and reestablish the protective aptitudes of ApoE. This appraisal represents the critical interactions of APOE and AD pathology, existing facts on ApoE levels in the central nervous system (CNS), and the credible active stratagems for AD therapy by aiming ApoE. This review also highlighted utmost ApoE targeting therapeutic tactics that are crucial for controlling Alzheimer’s pathogenesis.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid β

NFTs:

Neurofibrillary tangles

ApoE:

Apolipoprotein E

References

  1. 1.

    Uddin MS, Mamun AA, Asaduzzaman M, Hosn F, Sufian MA, Takeda S et al (2018) Spectrum of disease and prescription pattern for outpatients with neurological disorders: an empirical pilot study in Bangladesh. Ann Neurosci 25(1):25–37.

  2. 2.

    Uddin M, Stachowiak A, Mamun AA, Tzvetkov NT, Takeda S, Atanasov AG et al (2018) Autophagy and Alzheimer’s disease: from molecular mechanisms to therapeutic implications. Front Aging Neurosci 10(4): 1–18.

  3. 3.

    Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2):106–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362(4):329–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Uddin MS, Mamun AA, Kabir MT, Nasrullah M, Wahid F, Begum MM et al (2017) Neurochemistry of neurochemicals: messengers of brain functions. J Intell Dis-Diag Tre 5(4): 137–151.

  6. 6.

    Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T et al (2007) Reducing endogenous tau ameliorates amyloid ß-induced deficits in an Alzheimer’s disease mouse model. Science 316(5825):750–754.

  7. 7.

    Uddin MS, Mamun AA, Hossain MS, Akter F, Iqbal MA, Asaduzzaman M (2016) Exploring the effect of Phyllanthus emblica L. on cognitive performance, brain antioxidant markers and acetylcholinesterase activity in rats: promising natural gift for the mitigation of Alzheimer’s disease. Ann Neurosci 23(4):218–229

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158

    Article  Google Scholar 

  9. 9.

    Waring SC, Rosenberg RN (2008) Genome-wide association studies in Alzheimer disease. Arch Neurol 65(3):329–334

    Article  Google Scholar 

  10. 10.

    Blennow KdeLeon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368(9533):387–403

    Article  CAS  Google Scholar 

  11. 11.

    Bekris LM, Yu CE, Bird TD, Tsuang DW (2010) Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 23(4):213–227

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Zhang YW, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Mol Brain 4(1):3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ryan NS, Rossor MN (2010) Correlating familial Alzheimer’s disease gene mutations with clinical phenotype. Biomark Med 4(1):99–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Uddin MS, Haque A, Mamun AA, Iqbal MA, Kabir MT, Rony RK et al (2016). Searching the linkage between high fat diet and Alzheimer’s disease: a debatable proof stand for ketogenic diet to alleviate symptoms of Alzheimer’s patient with APOE ε4 allele. J Neurol Neurophysiol 7(5):1–9.

  15. 15.

    Zhang L, Hong H (2015) Genomic discoveries and personalized medicine in neurological diseases. Pharmaceutics 7(4):542–553

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Gureje O, Ogunniyi A, Baiyewu O, Price B, Unverzagt FW, Evans RM et al (2006) APOE ε4 is not associated with Alzheimer’s disease in elderly Nigerians. Ann Neurol 59(1):182–185.

  17. 17.

    Uddin MS, Asaduzzaman M, Mamun AA, Iqbal MA, Wahid F, Rony RK (2016) Neuroprotective activity of Asparagus racemosus Linn. against ethanol-induced cognitive impairment and oxidative stress in rats brain: auspicious for controlling the risk of Alzheimer’s disease. J Alzheimers Dis Parkinsonism 6(4):1–10

    Article  Google Scholar 

  18. 18.

    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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Hohman TJ, Dumitrescu L, Oksol A, Wagener M, Gifford KA, Jefferson AL et al (2017) APOE allele frequencies in suspected non-amyloid pathophysiology (SNAP) and the prodromal stages of Alzheimer’s disease. PLoS One 12(11):e0188501.

  20. 20.

    Xu X (2009) γ-Secretase catalyzes sequential cleavages of the AβPP transmembrane domain. J Alzheimers Dis 16(2):211–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Myers RH, Schaefer EJ, Wilson PWF, d'Agostino R, Ordovas JM, Espino A et al (1996) Apolipoprotein E element 4 association with dementia in a population-based study: The Framingham Study. Neurology 46(3):673–677.

  22. 22.

    Nuriel T, Angulo SL, Khan U, Ashok A, Chen Q, Figueroa HY et al (2017) Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology. Nat Commun 8(1):1464.

  23. 23.

    Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R et al (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA 278(16):1349–1356.

  24. 24.

    Sepehrnia B, Kamboh MI, Adams-Campbell LL, Bunker CH, Nwankwo M, Majumder P. P et al (1989) Genetic studies of human apolipoproteins. X. The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks. Am J Hum Genet 45(4):586.

  25. 25.

    Hendrie HC, Ogunniyi A, Hall KS, Baiyewu O, Unverzagt FW, Gureje O et al (2001) Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana. JAMA 285(6):739–747

    Article  CAS  Google Scholar 

  26. 26.

    Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K et al (2002) Apolipoprotein E ϵ4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med 137(3):149–155

    Article  CAS  Google Scholar 

  27. 27.

    Wisniewski T, Frangione B (1992) Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett 135(2):235–238

    Article  CAS  Google Scholar 

  28. 28.

    Hauser PS, Ryan RO (2013) Impact of apolipoprotein E on Alzheimer’s disease. Curr Alzheimer Res 10(8):809–817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC et al (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 7(2):180–184.

  30. 30.

    Howland DS, Trusko SP, Savage MJ, Reaume AG, Lang DM, Hirsch JD et al (1998) Modulation of secreted β-amyloid precursor protein and amyloid β-peptide in brain by cholesterol. J Biol Chem 273(26):16576–16582.

  31. 31.

    Ye S, Huang Y, Müllendorff K, Dong L, Giedt G, Meng EC et al (2005) Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target. Proc Natl Acad Sci U S A 102(51):18700–18705.

  32. 32.

    Hopkins PC, Sáinz-Fuertes R, Lovestone S (2011) The impact of a novel apolipoprotein E and amyloid-β protein precursor-interacting protein on the production of amyloid-β. J Alzheimers Dis 26(2):239–253

    Article  CAS  Google Scholar 

  33. 33.

    Huang Y-WA, Zhou B, Wernig M, Südhof TC (2017) ApoE2, ApoE3 and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell 168(3):427–441.e21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, Bender M et al (1997) Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nat Genet 17(3):263.

  35. 35.

    Irizarry MC, Rebeck GW, Cheung B, Bales K, Paul SM, Holzman D et al (2000) Modulation of Aβ deposition in APP transgenic mice by an apolipoprotein E null background. Ann N Y Acad Sci 920(1):171–178.

  36. 36.

    Holtzman DM, Bales KR, Wu S, Bhat P, Parsadanian M, Fagan AM et al (1999) Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer’s disease. J Clin Invest 103(6):R15-R21.

  37. 37.

    Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM et al (2005) Human apolipoprotein E4 alters the amyloid-β 40: 42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci 25(11):2803–2810.

  38. 38.

    Harper JD, Lansbury PT Jr (1997) Models of amyloid seeding in Alzheimer’s disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem 66(1):385–407

    Article  CAS  Google Scholar 

  39. 39.

    Chan W, Fornwald J, Brawner M, Wetzel R (1996) Native complex formation between apolipoprotein E isoforms and the Alzheimer’s disease peptide Aβ. Biochemistry 35(22):7123–7130

    Article  CAS  Google Scholar 

  40. 40.

    Castano EM, Prelli F, Wisniewski T, Golabek A, Kumar RA, Soto C et al (1995) Fibrillogenesis in Alzheimer’s disease of amyloid β peptides and apolipoprotein E. Biochem J 306(2):599–604.

  41. 41.

    Ma J, Yee A, Brewer HB Jr, Das S, Potter H (1994) Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments. Nature 372(6501):92

    Article  CAS  Google Scholar 

  42. 42.

    Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO et al (2012) Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J Neurosci 32(43):15181–15192.

  43. 43.

    Cerf E, Gustot A, Goormaghtigh E, Ruysschaert JM, Raussens V (2011) High ability of apolipoprotein E4 to stabilize amyloid-β peptide oligomers, the pathological entities responsible for Alzheimer’s disease. FASEB J 25(5):1585–1595

    Article  CAS  Google Scholar 

  44. 44.

    Kanekiyo T, Xu H, Bu G (2014) ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron 81(4):740–754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Naiki H, Gejyo F, Nakakuki K (1997) Concentration-dependent inhibitory effects of apolipoprotein E on Alzheimer’s β-amyloid fibril formation in vitro. Biochemistry 36(20):6243–6250

    Article  CAS  Google Scholar 

  46. 46.

    Wood SJ, Chan W, Wetzel R (1996) An ApoE-Aβ inhibition complex in Aβ fibril extension. Chem Biol 3(11):949–956

    Article  CAS  Google Scholar 

  47. 47.

    Golabek AA, Soto C, Vogel T, Wisniewski T (1996) The interaction between apolipoprotein E and Alzheimers amyloid-peptide is dependent on-peptide conformation. J Biol Chem 271(18):10602–10606

    Article  CAS  Google Scholar 

  48. 48.

    Hatters DM, Zhong N, Rutenber E, Weisgraber KH (2006) Amino-terminal domain stability mediates apolipoprotein E aggregation into neurotoxic fibrils. J Mol Biol 361(5):932–944

    Article  CAS  Google Scholar 

  49. 49.

    Bales KR, Liu F, Wu S, Lin S, Koger D, DeLong C et al (2009) Human APOE isoform-dependent effects on brain β-amyloid levels in PDAPP transgenic mice. J Neurosci 29(21):6771–6779.

  50. 50.

    Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J et al (2006) Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26(40):10129–10140.

  51. 51.

    Youmans KL. Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M et al (2012) APOE4-specific changes in Aβ accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem 287(50):41774–41786.

  52. 52.

    Hatami A, Monjazeb S, Milton S, Glabe CG (2017) Familial Alzheimer’s disease mutations within the amyloid precursor protein alter the aggregation and conformation of the amyloid-β peptide. J Biol Chem 292(8):3172–3185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    He X, Cooley K, Chung CH, Dashti N, Tang J (2007) Apolipoprotein receptor 2 and X11α/β mediate apolipoprotein E-induced endocytosis of amyloid-β precursor protein and β-secretase, leading to amyloid-β production. J Neurosci 27(15):4052–4060

    Article  CAS  Google Scholar 

  54. 54.

    Weisgraber KH, Pitas RF, Mahley RW (1994) Lipoproteins, neurobiology, and Alzheimer’s disease: structure and function of apolipoprotein E. Curr Opin Struct Biol 4(4):507–515

    Article  CAS  Google Scholar 

  55. 55.

    Biere AL, Ostaszewski B, Zhao H, Gillespie S, Younkin SG, Selkoe DJ (1995) Co-expression of β-amyloid precursor protein (βAPP) and apolipoprotein E in cell culture: analysis of βAPP processing. Neurobiol Dis 2(3):177–187

    Article  CAS  Google Scholar 

  56. 56.

    Irizarry MC, Deng A, Lleo A, Berezovska O, Von Arnim CA, Martin-Rehrmann M et al (2004) Apolipoprotein E modulates γ-secretase cleavage of the amyloid precursor protein. J Neurochem 90(5):1132–1143.

  57. 57.

    Beffert U, Aumont N, Dea D, Lussier-Cacan S, Davignon J, Poirier J (1998) β-amyloid peptides increase the binding and internalization of apolipoprotein E to hippocampal neurons. J Neurochem 70(4):1458–1466

    Article  CAS  Google Scholar 

  58. 58.

    Nielsen HM, Veerhuis R, Holmqvist BO, Janciauskiene S (2009) Binding and uptake of Aβ1-42 by primary human astrocytes in vitro. Glia 57(9):978–988

    Article  Google Scholar 

  59. 59.

    Yamauchi K, Tozuka M, Hidaka H, Nakabayashi T, Sugano M, Katsuyama T (2002) Isoform-specific effect of apolipoprotein E on endocytosis of fl-amyloid in cultures of neuroblastoma cells. Ann Clin Lab Sci 32(1):65–74

    CAS  Google Scholar 

  60. 60.

    Jiang Q, Lee CD, Mandrekar S, Wilkinson B, Cramer P, Zelcer N et al (2008) ApoE promotes the proteolytic degradation of Aβ. Neuron 58(5):681–693.

  61. 61.

    Koistinaho M, Lin S, Wu XIN, Esterman M, Koger D, Hanson J et al (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides. Nat Med 10(7):719.

  62. 62.

    Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J et al (1999) Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 96(26):15233–15238.

  63. 63.

    Dodart JC, Bales KR, Johnstone EM, Little SP, Paul SM (2002) Apolipoprotein E alters the processing of the β-amyloid precursor protein in APPV717F transgenic mice. Brain Res 955(1–2):191–199

    Article  CAS  Google Scholar 

  64. 64.

    DeMattos RB, Cirrito JR, Parsadanian M, May PC, O'Dell MA, Taylor JW et al (2004) ApoE and clusterin cooperatively suppress Aβ levels and deposition: evidence that ApoE regulates extracellular Aβ metabolism in vivo. Neuron 41(2):193–202.

  65. 65.

    Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178–201

    Article  CAS  Google Scholar 

  66. 66.

    Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB et al (2008) apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain. J Clin Invest 118(12):4002–4013.

  67. 67.

    Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R et al (2007) Transport pathways for clearance of human Alzheimer’s amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 27(5):909–918.

  68. 68.

    Ito S, Ohtsuki S, Kamiie J, Nezu Y, Terasaki T (2007) Cerebral clearance of human amyloid-β peptide (1–40) across the blood–brain barrier is reduced by self-aggregation and formation of low-density lipoprotein receptor-related protein-1 ligand complexes. J Neurochem 103(6):2482–2490

    Article  CAS  Google Scholar 

  69. 69.

    Ji Y, Permanne B, Sigurdsson EM, Holtzman D, Wisniewski T (2001) Amyloid β40/42 clearance across the blood-brain barrier following intra-ventricular injections in wild-type, apoE knock-out and human apoE3 or E4 expressing transgenic mice. J Alzheimers Dis 3(1):23–30

    Article  CAS  Google Scholar 

  70. 70.

    Martel CL, Mackic JB, Matsubara E, Governale S, Miguel C, Miao W et al (1997) Isoform-specific effects of apolipoproteins E2, E3, and E4 on cerebral capillary sequestration and blood-brain barrier transport of circulating Alzheimer’s amyloid β. J Neurochem 69(5):1995–2004.

  71. 71.

    Liu CC, Hu J, Zhao N, Wang J, Wang N, Cirrito JR et al (2017) Astrocytic LRP1 mediates brain Aβ clearance and impacts amyloid deposition. J Neurosci 37(15):4023–4031.

  72. 72.

    Rebeck GW (2017) The role of APOE on lipid homeostasis and inflammation in normal brains. J Lipid Res 58(8):1493–1499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K et al (2017) Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathol 133(5):839–856.

  74. 74.

    Agosta F, Vossel KA, Miller BL et al (2009) Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. Proc Natl Acad Sci U S A 106(6):2018–2022.

  75. 75.

    Riemenschneider M, Diehl J, Muller U, Forstl H, Kurz A (2002) Apolipoprotein E polymorphism in German patients with frontotemporal degeneration. J Neurol Neurosurg Psychiatry 72(5):639–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Srinivasan R, Davidson Y, Gibbons L et al (2006) The apolipoprotein E ε4 allele selectively increases the risk of frontotemporal lobar degeneration in males. J Neurol Neurosurg Psychiatry 77(2):154–158.

  77. 77.

    Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong LM, Jakes R et al (1994) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc Natl Acad Sci U S A 91(23):11183–11186.

  78. 78.

    Chang S, ran MT, Miranda RD, Balestra ME, Mahley RW, Huang Y (2005) Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci U S A 102(51):18694–18699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Harris FM, Brecht WJ, Xu Q, Mahley RW, Huang Y (2004) Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc. J Biol Chem 279(43):44795–44801

    Article  CAS  Google Scholar 

  80. 80.

    Hoe HS, Harris DC, Rebeck GW (2005) Multiple pathways of apolipoprotein E signaling in primary neurons. J Neurochem 93(1):145–155

    Article  CAS  Google Scholar 

  81. 81.

    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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W et al (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549(7673):523.

  83. 83.

    Benskey MJ, Perez RG, Manfredsson FP (2016) The contribution of alpha synuclein to neuronal survival and function—implications for Parkinson’s disease. J Neurochem 137:331–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Huynh TPV, Davis AA, Ulrich JD, Holtzman DM (2017) Apolipoprotein E and Alzheimer’s disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins. J Lipid Res 58(5):824–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Gallardo G, Schlüter OM, Südhof TC (2008) A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides. Nat Neurosci 11(3):301

    Article  CAS  Google Scholar 

  86. 86.

    Emamzadeh FN, Aojula H, McHugh PC, Allsop D (2016) Effects of different isoforms of apoE on aggregation of the α-synuclein protein implicated in Parkinson’s disease. Neurosci Lett 618:146–151

    Article  CAS  Google Scholar 

  87. 87.

    Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252

    Article  CAS  Google Scholar 

  88. 88.

    Al-Wandi A, Ninkina N, Millership S, Williamson SJ, Jones PA, Buchman VL (2010) Absence of alpha-synuclein affects dopamine metabolism and synaptic markers in the striatum of aging mice. Neurobiol Aging 31:796–804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Gureviciene I, Gurevicius K, Tanila H (2007) Role of alpha-synuclein in synaptic glutamate release. Neurobiol Dis 28:83–89

    Article  CAS  Google Scholar 

  90. 90.

    Chen RH, Wislet-Gendebien S, Samuel F, Visanji NP, Zhang G, Marsilio D (2013) Alpha-Synuclein membrane association is regulated by the Rab3a recycling machinery and presynaptic activity. J Biol Chem 288:7438–7449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Teter B, Xu PT, Gilbert JR, Roses AD, Galasko D, Cole GM (2002) Defective neuronal sprouting by human apolipoprotein E4 is a gain-of-negative function. J Neurosci Res 68:331–336

    Article  CAS  Google Scholar 

  92. 92.

    Sen A, Alkon DL, Nelson TJ (2012) Apolipoprotein E3 (ApoE3) but not ApoE4 protects against synaptic loss through increased expression of protein kinase C epsilon. J Biol Chem 287:15947–15958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Bar R, Boehm-Cagan A, Luz I, Kleper-Wall Y, Michaelson DM (2018) The effects of apolipoprotein E genotype, α-synuclein deficiency, and sex on brain synaptic and Alzheimer’s disease–related pathology. Alzheimers Dement (Amst) 10:1–11

    Google Scholar 

  94. 94.

    Zheng WH, Bastianetto S, Mennicken F, Ma W, Kar S (2002) Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience 115:201–211

    Article  CAS  Google Scholar 

  95. 95.

    Austin SA, Floden AM, Murphy EJ, Combs CK (2006) Alpha-synuclein expression modulates microglial activation phenotype. J Neurosci 26(41):10558–10563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Austin SA, Rojanathammanee L, Golovko MY, Murphy EJ, Combs CK (2011) Lack of alpha-synuclein modulates microglial phenotype in vitro. Neurochem Res 36:994–1004

    Article  CAS  Google Scholar 

  97. 97.

    Li X, Montine KS, Keene CD, Montine TJ (2015) Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia. FASEB J 29:1754–1762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Ouberai MM, Wang J, Swann MJ et al (2013) α-Synuclein senses lipid packing defects and induces lateral expansion of lipids leading to membrane remodeling. J Biol Chem 288(29):20883–20895.

  99. 99.

    Castagnet PI, Golovko MY, Barceló-Coblijn GC, Nussbaum RL, Murphy EJ (2005) Fatty acid incorporation is decreased in astrocytes cultured from alpha-synuclein gene-ablated mice. J Neurochem 94(3):839–849

    Article  CAS  Google Scholar 

  100. 100.

    Hu J, Liu C-C, Chen X-F, Zhang Y, Xu H, Bu G (2015) Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice. Mol Neurodegener 10:6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Ardura-Fabregat A, Boddeke EWGM, Boza-Serrano A, Brioschi S, Castro-Gomez S, Ceyzériat K et al (2017) Targeting Neuroinflammation to treat Alzheimer’s disease. CNS Drugs, 31(12):1057–1082.

  102. 102.

    LaDu MJ, Shah JA, Reardon CA, Getz GS, Bu G, Hu J et al (2001) Apolipoprotein E and apolipoprotein E receptors modulate Aβ-induced glial neuroinflammatory responses. Neurochem Int 39(5–6):427–434.

  103. 103.

    Lynch JR, Morgan D, Mance J, Matthew WD, Laskowitz DT (2001) Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response. J Neuroimmunol 114(1):107–113

    Article  CAS  Google Scholar 

  104. 104.

    Lynch JR, Tang W, Wang H, Vitek MP, Bennett ER, Sullivan PM et al (2003) APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem 278(49):48529–48533.

  105. 105.

    Ringman JM, Elashoff D, Geschwind DH, Welsh BT, Gylys KH, Lee C et al (2012) Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype. Arch Neurol 69(6):757–764.

  106. 106.

    Szekely CA, Breitner JC, Fitzpatrick AL, Rea TD, Psaty BM, Kuller LH et al (2008) NSAID use and dementia risk in the cardiovascular health study role of APOE and NSAID type. Neurology 70(1):17–24.

  107. 107.

    Svennerholm L, Gottfries CG (1994) Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late-onset form (type II). J Neurochem 62(3):1039–1047

    Article  CAS  Google Scholar 

  108. 108.

    Riddell DR, Zhou H, Atchison K, Warwick HK, Atkinson PJ, Jefferson J et al (2008) Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J Neurosci 28(45):11445–11453.

  109. 109.

    Rapp A, Gmeiner B, Hüttinger M (2006) Implication of apoE isoforms in cholesterol metabolism by primary rat hippocampal neurons and astrocytes. Biochimie 88(5):473–483

    Article  CAS  Google Scholar 

  110. 110.

    Hamanaka H, Katoh-Fukui Y, Suzuki K, Kobayashi M, Suzuki R, Motegi Y et al (2000) Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice. Hum Mol Genet 9(3):353–361.

  111. 111.

    Moser VA, Pike CJ (2017) Obesity accelerates Alzheimer-related pathology in APOE4 but not APOE3 mice. eNeuro 4(3):ENEURO-0077

    Article  Google Scholar 

  112. 112.

    Chen Y, Durakoglugil MS, Xian X, Herz J (2010) ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci U S A 107(26):12011–12016

    Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Buttini M, Yu GQ, Shockley K, Huang Y, Jones B, Masliah E et al (2002) Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid β peptides but not on plaque formation. J Neurosci 22(24):10539–10548.

  114. 114.

    Sen A, Alkon DL, Nelson TJ (2012) Apolipoprotein E3 (apoE3) but not apoE4 protects against synaptic loss through increased expression of protein kinase Cϵ. J Biol Chem 287(19):15947–15958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Qiao F, Gao XP, Yuan L, Cai HY, Qi JS (2014) Apolipoprotein E4 impairs in vivo hippocampal long-term synaptic plasticity by reducing the phosphorylation of CaMKIIα and CREB. J Alzheimers Dis 41(4):1165–1176

    Article  CAS  Google Scholar 

  116. 116.

    Hwang KD, Bak MS, Kim SJ, Rhee S, Lee YS (2017) Restoring synaptic plasticity and memory in mouse models of Alzheimer’s disease by PKR inhibition. Mol Brain 10(1):57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Sando SB, Melquist S, Cannon A, Hutton ML, Sletvold O, Saltvedt I et al (2008) APOE ε4 lowers age at onset and is a high risk factor for Alzheimer’s disease; a case control study from Central Norway. BMC Neurol 8(1):9.

  118. 118.

    Quiroga P, Calvo C, Albala C, Urquidi J, Santos J, Pérez H et al (1999) Apolipoprotein E polymorphism in elderly Chilean people with Alzheimer’s disease. Neuroepidemiology 18(1):48–52.

  119. 119.

    Kim KW, Jhoo JH, Lee KU, Lee DY, Lee JH, Youn JY et al (1999) Association between apolipoprotein E polymorphism and Alzheimer’s disease in Koreans. Neurosci Lett 277(3):145–148.

  120. 120.

    Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39(1):17

    Article  CAS  Google Scholar 

  121. 121.

    Raygani AV, Zahrai M, Raygani AV, Doosti M, Javadi E, Rezaei M et al (2005) Association between apolipoprotein E polymorphism and Alzheimer disease in Tehran, Iran. Neurosci Lett 375(1):1–6.

  122. 122.

    Rassas AA, Khiari HM, Fredj SH, Sahnoun S, Batti H, Zakraoui NO et al (2012) High APOE epsilon 4 allele frequencies associated with Alzheimer disease in a Tunisian population. Neurol Sci 33(1):33–37.

  123. 123.

    Kline A (2012) Apolipoprotein E, amyloid-ß clearance and therapeutic opportunities in Alzheimer’s disease. Alzheimers Res Ther 4(4):32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Fukumoto H, Ingelsson M, Gårevik N, Wahlund LO, Nukina N, Yaguchi Y et al (2003) APOE ε3/ε4 heterozygotes have an elevated proportion of apolipoprotein E4 in cerebrospinal fluid relative to plasma, independent of Alzheimer’s disease diagnosis. Exp Neurol 183(1):249–253.

  125. 125.

    Bekris LM, Millard SP, Galloway NM, Vuletic S, Albers JJ, Li G et al (2008) Multiple SNPs within and surrounding the apolipoprotein E gene influence cerebrospinal fluid apolipoprotein E protein levels. J Alzheimers Dis 13(3):255–266.

  126. 126.

    Wahrle SE, Shah AR, Fagan AM, Smemo S, Kauwe JS, Grupe A et al (2007) Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms. Mol Neurodegener 2(1):7.

  127. 127.

    Talwar P, Sinha J, Grover S, Agarwal R, Kushwaha S, Srivastava MP et al (2016) Meta-analysis of apolipoprotein E levels in the cerebrospinal fluid of patients with Alzheimer’s disease. J Neurol Sci 360:179–187.

  128. 128.

    Beffert U, Cohn JS, Petit-Turcotte C, Tremblay M, Aumont N, Ramassamy C et al (1999) Apolipoprotein E and β-amyloid levels in the hippocampus and frontal cortex of Alzheimer’s disease subjects are disease-related and apolipoprotein E genotype dependent. Brain Res 843(1–2):87–94.

  129. 129.

    Bray NJ, Jehu L, Moskvina V, Buxbaum JD, Dracheva S, Haroutunian V et al (2004) Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes. Hum Mol Genet 13(22):2885–2892.

  130. 130.

    Pirttilä T, Soininen H, Heinonen O, Lehtimäki T, Bogdanovic N, Paljärvi L et al (1996) Apolipoprotein E (apoE) levels in brains from Alzheimer disease patients and controls. Brain Res 722(1–2):71–77.

  131. 131.

    Tachibana M, Shinohara M, Yamazaki Y, Liu CC, Rogers J, Bu G et al (2016) Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Exp Neurol 277:1–9.

  132. 132.

    Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S et al (2010) ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J Biol Chem 285(44):34144–34154.

  133. 133.

    Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC et al (2005) The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer’s disease. J Biol Chem 280(6):4079–4088.

  134. 134.

    Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, Warwick HK et al (2007) The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease. Mol Cell Neurosci 34(4):621–628.

  135. 135.

    Vanmierlo T, Rutten K, Dederen J, Bloks VW, van Vark-van der Zee LC, Kuipers F et al (2011) Liver X receptor activation restores memory in aged AD mice without reducing amyloid. Neurobiol Aging 32(7):1262–1272.

  136. 136.

    Skerrett R, Pellegrino MP, Casali BT, Taraboanta L, Landreth GE (2015) Combined liver X receptor/peroxisome proliferator-activated receptor gamma agonist treatment reduces amyloid beta levels and improves behavior in amyloid precursor protein/Presenilin 1 mice. J Biol Chem 290(35):21591–21602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Hong C, Tontonoz P (2014) Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat Rev Drug Discov 13(6):433–444

    Article  CAS  Google Scholar 

  138. 138.

    Osei-Hwedieh DO, Amar M, Sviridov D, Remaley AT (2011) Apolipoprotein mimetic peptides: mechanisms of action as anti-atherogenic agents. Pharmacol Ther 130(1):83–91

    Article  CAS  Google Scholar 

  139. 139.

    Ghosal K, Stathopoulos A, Thomas D, Phenis D, Vitek MP, Pimplikar SW (2013) The apolipoprotein-E-mimetic COG112 protects amyloid precursor protein intracellular domain-overexpressing animals from Alzheimer’s disease-like pathological features. Neurodegener Dis 12(1):51–58

    Article  CAS  Google Scholar 

  140. 140.

    Vitek MP, Christensen DJ, Wilcock D, Davis J, Van Nostrand WE, Li FQ et al (2012) APOE-mimetic peptides reduce behavioral deficits, plaques and tangles in Alzheimer’s disease transgenics. Neurodegener Dis 10(1–4):122–126.

  141. 141.

    Minami SS, Cordova A, Cirrito JR, Tesoriero JA, Babus LW, Davis GC et al (2010) ApoE mimetic peptide decreases Abeta production in vitro and in vivo. Mol Neurodegener 5:16.

  142. 142.

    Handattu SP, Monroe CE, Nayyar G, Palgunachari MN, Kadish I, van Groen T et al (2013) In vivo and in vitro effects of an apolipoprotein e mimetic peptide on amyloid-beta pathology. J Alzheimers Dis 36(2):335–347.

  143. 143.

    Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE et al (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335(6075):1503–1506.

  144. 144.

    Cummings JL, Zhong K, Kinney JW, Heaney C, Moll-Tudla J, Joshi A et al (2016) Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease. Alzheimers Res Ther 8(1):4.

  145. 145.

    Boehm-Cagan A, Michaelson DM (2014) Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. J Neurosci 34(21):7293–7301

    Article  CAS  Google Scholar 

  146. 146.

    Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M, Guridi M et al (2013) Blocking the interaction between apolipoprotein E and Abeta reduces intraneuronal accumulation of Abeta and inhibits synaptic degeneration. Am J Pathol 182(5):1750–1768.

  147. 147.

    Sadowski MJ, Pankiewicz J, Scholtzova H, Mehta PD, Prelli F, Quartermain D et al (2006) Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer’s disease. Proc Natl Acad Sci U S A 103(49):18787–18792.

  148. 148.

    Liu S, Breitbart A, Sun Y, Mehta PD, Boutajangout A, Scholtzova H et al (2014) Blocking the apolipoprotein E/amyloid beta interaction in triple transgenic mice ameliorates Alzheimer’s disease related amyloid beta and tau pathology. J Neurochem 128(4):577–591.

  149. 149.

    Pankiewicz JE, Guridi M, Kim J, Asuni AA, Sanchez S, Sullivan PM et al (2014) Blocking the apoE/Abeta interaction ameliorates Abeta-related pathology in APOE epsilon2 and epsilon4 targeted replacement Alzheimer model mice. Acta Neuropathol Commun 2:75.

  150. 150.

    Hao J, Zhang W, Zhang P, Liu R, Liu L, Lei G et al (2010) Abeta20-29 peptide blocking apoE/Abeta interaction reduces full-length Abeta42/40 fibril formation and cytotoxicity in vitro. Neuropeptides 44(4):305–313.

  151. 151.

    Bien-Ly N, Gillespie AK, Walker D, Yoon SY, Huang Y (2012) Reducing human apolipoprotein E levels attenuates age-dependent Abeta accumulation in mutant human amyloid precursor protein transgenic mice. J Neurosci 32(14):4803–4811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Kim J, Jiang H, Park S, Eltorai AE, Stewart FR, Yoon H et al (2011) Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis. J Neurosci 31(49):18007–18012.

  153. 153.

    Liao F, Hori Y, Hudry E, Bauer AQ, Jiang H, Mahan TE et al (2014) Anti-ApoE antibody given after plaque onset decreases Abeta accumulation and improves brain function in a mouse model of Abeta amyloidosis. J Neurosci ;34(21):7281–7292.

  154. 154.

    Kim J, Eltorai AE, Jiang H, Liao F, Verghese PB, Stewart FR et al (2012) Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Abeta amyloidosis. J Exp Med 209(12):2149–2156.

  155. 155.

    Zhong N, Scearce-Levie K, Ramaswamy G, Weisgraber KH (2008) Apolipoprotein E4 domain interaction: synaptic and cognitive deficits in mice. Alzheimers Dement 4:179–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Mahley RW, Huang Y (2012) Small-molecule structure correctors target abnormal protein structure and function: structure corrector rescue of apolipoprotein E4-associated neuropathology. J Med Chem 55:8997–9008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Chen HK, Liu Z, Meyer-Franke A, Brodbeck J, Miranda RD, McGuire JG et al (2012) Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons. J Biol Chem 287:5253–5266.

  158. 158.

    Dow LE, Fisher J, O'Rourke KP, Muley A, Kastenhuber ER, Livshits G et al (2015) Inducible in vivo genome editing with CRISPR-Cas9. Nat Biotechnol 33:390–394.

  159. 159.

    Zhou W, Scott SA, Shelton SB, Crutcher KA (2006) Cathepsin D-mediated proteolysis of apolipoprotein E: possible role in Alzheimer’s disease. Neuroscience 143(3):689–701

    Article  CAS  Google Scholar 

  160. 160.

    Castellano JM, Deane R, Gottesdiener AJ, Verghese PB, Stewart FR, West T et al (2012) Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Abeta clearance in a mouse model of beta-amyloidosis. Proc Natl Acad Sci U S A 109:15502–15507.

  161. 161.

    Liu CC, Zhao N, Yamaguchi Y, Cirrito JR, Kanekiyo T, Holtzman DM et al (2016) Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-beta clearance and aggregation in Alzheimer’s disease. Sci Transl Med 8:332ra344.

  162. 162.

    Bu G (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10:333–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Kanekiyo T, Xu H, Bu G (2014) ApoE and Abeta in Alzheimer’s disease: accidental encounters or partners? Neuron 81(4):740–754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Getz GS, Reardon CA (2009) Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall. J Lipid Res 50(Suppl):S156–S161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Chan ES, Shetty MS, Sajikumar S, Chen C, Soong TW, Wong B-S (2016) ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer’s disease mouse model. Sci Rep 6:26119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Newport MT, VanItallie TB, Kashiwaya Y, King MT, Veech RL (2015) A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer’s. Alzheimers Dement 11(1):99–103

    Article  Google Scholar 

  167. 167.

    Krikorian R, Shidler MD, Dangelo K, Couch SC, Benoit SC, Clegg DJ (2012) Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol Aging 33(2):425.e19–425.e27

    Article  CAS  Google Scholar 

  168. 168.

    Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z et al (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485(7399):512–516.

  169. 169.

    Pankiewicz JE, Sadowski MJ (2017) APOE genotype and Alzheimer’s immunotherapy. Oncotarget 8(25):39941–39942

    Article  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Pankiewicz JE, Baquero-Buitrago J, Sanchez S et al (2017) APOE genotype differentially modulates effects of anti-Aβ, passive immunization in APP transgenic mice. Mol Neurodegener 12:12.

  171. 171.

    Cramer PE, Cirrito JR, Wesson DW, Lee CD, Karlo JC, Zinn AE et al (2012) ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335(6075):1503–1506.

  172. 172.

    Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, Warwick HK et al (2007) The LXR agonist TO901317 selectively lowers hippocampal Aβ42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease. Mol Cell Neurosci 34(4):621–628.

  173. 173.

    Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A et al (2008) Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 118(2):671–682.

  174. 174.

    Kim J, Jiang H, Park S, Eltorai AE, Stewart FR, Yoon H et al (2011) Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. J Neurosci 31(49):18007–18012.

  175. 175.

    Kim J, Eltorai AE, Jiang H, Liao F, Verghese PB, Kim J et al (2012) Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis. J Exp Med 209(12):2149–2156.

  176. 176.

    Sadowski M, Pankiewicz J, Scholtzova H, Ripellino JA, Li Y, Schmidt SD et al (2004) A synthetic peptide blocking the apolipoprotein E/β-amyloid binding mitigates β-amyloid toxicity and fibril formation in vitro and reduces β-amyloid plaques in transgenic mice. Am J Pathol 165(3):937–948.

  177. 177.

    Shinohara M, Sato N, Kurinami H, Takeuchi D, Takeda S, Shimamura M et al (2010) Reduction of brain β-amyloid (Aβ) by fluvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, through increase in degradation of amyloid precursor protein C-terminal fragments (APP-CTFs) and Aβ clearance. J Biol Chem 285(29):22091–22102.

  178. 178.

    Luz I, Liraz O, Michaelson DM (2016) An anti-apoE4 specific monoclonal antibody counteracts the pathological effects of apoE4 in vivo. Curr Alzheimer Res 13(8):918–929

    Article  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to the Department of Pharmacy, Southeast University, Dhaka, Bangladesh. The authors wish to thank the anonymous reviewer(s)/editor(s) of this article for their constructive reviews.

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This work was carried out in collaboration between all authors. MSU and GMA designed the study, wrote the protocol, and managed the analyses of the study. MSU, MTK, and AAM prepared the first draft of the manuscript. MMA-D, GEB, and GMA revised and improved the first draft. All authors read and approved the final submitted version of the manuscript.

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Correspondence to Md. Sahab Uddin or Ghulam Md Ashraf.

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Uddin, M.S., Kabir, M.T., Al Mamun, A. et al. APOE and Alzheimer’s Disease: Evidence Mounts that Targeting APOE4 may Combat Alzheimer’s Pathogenesis. Mol Neurobiol 56, 2450–2465 (2019). https://doi.org/10.1007/s12035-018-1237-z

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Keywords

  • APOE4
  • Senile plaques
  • Neurofibrillary tangles
  • Amyloid β
  • Tauopathy
  • Alzheimer’s disease