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Open Access 01-12-2017 | Research article

APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice

Authors: Joanna E Pankiewicz, Jairo Baquero-Buitrago, Sandrine Sanchez, Jennifer Lopez-Contreras, Jungsu Kim, Patrick M. Sullivan, David M. Holtzman, Martin J. Sadowski

Published in: Molecular Neurodegeneration | Issue 1/2017

Abstract

Background

APOE genotype is the foremost genetic factor modulating β-amyloid (Aβ) deposition and risk of sporadic Alzheimer’s disease (AD). Here we investigated how APOE genotype influences response to anti-Aβ immunotherapy.

Methods

APP_SW/PS1_dE9 (APP) transgenic mice with targeted replacement of the murine Apoe gene for human APOE alleles received 10D5 anti-Aβ or TY11-15 isotype control antibodies between the ages of 12 and 15 months.

Results

Anti-Aβ immunization decreased both the load of fibrillar plaques and the load of Aβ immunopositive plaques in mice of all APOE backgrounds. Although the relative reduction in parenchymal Aβ plaque load was comparable across all APOE genotypes, APP/ε4 mice showed the greatest reduction in the absolute Aβ plaque load values, given their highest baseline. The immunization stimulated phagocytic activation of microglia, which magnitude adjusted for the post-treatment plaque load was the greatest in APP/ε4 mice implying association between the ε4 allele and impaired Aβ phagocytosis. Perivascular hemosiderin deposits reflecting ensued microhemorrhages were associated with vascular Aβ (VAβ) and ubiquitously present in control mice of all APOE genotypes, although in APP/ε3 mice their incidence was the lowest. Anti-Aβ immunization significantly reduced VAβ burden but increased the number of hemosiderin deposits across all APOE genotypes with the strongest and the weakest effect in APP/ε2 and APP/ε3 mice, respectively.

Conclusions

Our studies indicate that APOE genotype differentially modulates microglia activation and Aβ plaque load reduction during anti-Aβ immunotherapy. The APOE ε3 allele shows strong protective effect against immunotherapy associated microhemorrhages; while, conversely, the APOE ε2 allele increases risk thereof.

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Selkoe DJ. SnapShot: pathobiology of Alzheimer’s disease. Cell. 2013;154:468.CrossRefPubMed

Selkoe DJ. Resolving controversies on the path to Alzheimer’s therapeutics. Nat Med. 2011;17:1060–65.CrossRefPubMed

Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362:329–44.CrossRefPubMed

Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–18.CrossRefPubMedPubMedCentral

Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33.CrossRefPubMedPubMedCentral

Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu ZX, Loetscher H, Santarelli L. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012;69:198–207.CrossRefPubMed

Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, Mathis CA, Blennow K, Barakos J, Okello AA, de LS RM, Liu E, Koller M, Gregg KM, Schenk D, Black R, Grundman M. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9:363–72.CrossRefPubMed

Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature. 2016;537:50–6.CrossRefPubMed

Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of alzheimer disease [In Process Citation]. Nat Med. 2000;6:916–19.CrossRefPubMed

10.

Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, Khan K, Kholodenko D, Lee C, Lee M, Motter R, Nguyen M, Reed A, Schenk D, Tang P, Vasquez N, Seubert P, Yednock T. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci U S A. 2003;100:2023–28.CrossRefPubMedPubMedCentral

11.

Seubert P, Barbour R, Khan K, Motter R, Tang P, Kholodenko D, Kling K, Schenk D, Johnson-Wood K, Schroeter S, Gill D, Jacobsen JS, Pangalos M, Basi G, Games D. Antibody capture of soluble Abeta does not reduce cortical Abeta amyloidosis in the PDAPP mouse. Neurodegener Dis. 2008;5:65–71.CrossRefPubMed

12.

Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T, Gill D, Basi G, Schenk D, Seubert P, Games D. Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci. 2008;28:6787–93.CrossRefPubMed

13.

Sperling RA, Jack Jr CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, Feldman HH, Schindler RJ. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367–85.CrossRefPubMedPubMedCentral

14.

Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241–49.CrossRefPubMedPubMedCentral

15.

Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, Van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurol. 2009;73:2061–70.CrossRef

16.

Sullivan PM, Mezdour H, Quarfordt SH, Maeda N. Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2. J Clin Invest. 1998;102:130–35.CrossRefPubMedPubMedCentral

17.

Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick RL, Quarfordt SH, Maeda N. Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem. 1997;272:17972–80.CrossRefPubMed

18.

Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:9649–53.CrossRefPubMedPubMedCentral

19.

Pankiewicz JE, Guridi M, Kim J, Asuni AA, Sanchez S, Sullivan PM, Holtzman DM, Sadowski MJ. Blocking the apoE/A-beta interaction ameliorates A-beta-related pathology in APOE epsilon 2 and epsilon 4 targeted replacement Alzheimer model mice. Acta Neuropathol Commun. 2014;2:75.PubMedPubMedCentral

20.

Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M, Guridi M, Asuni AA, Sullivan PM, Holtzman DM, Sadowski MJ. Blocking the Interaction between Apolipoprotein E and Abeta Reduces Intraneuronal Accumulation of Abeta and Inhibits Synaptic Degeneration. Am J Pathol. 2013;182:1750–68.CrossRefPubMedPubMedCentral

21.

Zago W, Schroeter S, Guido T, Khan K, Seubert P, Yednock T, Schenk D, Gregg KM, Games D, Bard F, Kinney GG. Vascular alterations in PDAPP mice after anti-Abeta immunotherapy: Implications for amyloid-related imaging abnormalities. Alzheimers Dement. 2013;9:S105–15.CrossRefPubMed

22.

Hartman RE, Izumi Y, Bales KR, Paul SM, Wozniak DF, Holtzman DM. Treatment with an amyloid-beta antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer’s disease. J Neurosci. 2005;25:6213–20.CrossRefPubMed

23.

Asuni AA, Guridi M, Pankiewicz JE, Sanchez S, Sadowski MJ. Modulation of amyloid precursor protein expression reduces beta-amyloid deposition in a mouse model. Ann Neurol. 2014;75:684–99.CrossRefPubMedPubMedCentral

24.

Sadowski MJ, Pankiewicz J, Scholtzova H, Mehta PD, Prelli F, Quartermain D, Wisniewski T. Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103:18787–92.CrossRefPubMedPubMedCentral

25.

Fryer JD, Taylor JW, DeMattos RB, Bales KR, Paul SM, Parsadanian M, Holtzman DM. Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein Transgenic mice. J Neurosci. 2003;23:7889–96.PubMed

26.

Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-A beta immunotherapy. Science. 2002;298:1379.CrossRefPubMed

27.

Wisniewski HM, Sadowski M, Jakubowska-Sadowska K, Tarnawski M, Wegiel J. Diffuse, lake-like amyloid-beta deposits in the parvopyramidal layer of the presubiculum in Alzheimer disease. J Neuropath Exp Neurol. 1998;57:674–83.CrossRefPubMed

28.

Cortes-Sol A, Lara-Garcia M, Alvarado M, Hudson R, Berbel P, Pacheco P. Inner capillary diameter of hypothalamic paraventricular nucleus of female rat increases during lactation. BMC Neurosci. 2013;14:7.CrossRefPubMedPubMedCentral

29.

Thal DR, Capetillo-Zarate E, Larionov S, Staufenbiel M, Zurbruegg S, Beckmann N. Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances. Neurobiol Aging. 2009;30:1936–48.CrossRefPubMed

30.

Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S. Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res. 1998;57:1–9.CrossRefPubMed

31.

Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, Neal JW, Love S, Nicoll JA, Boche D. Inflammatory components in human Alzheimer’s disease and after active amyloid-beta42 immunization. Brain. 2013;136:2677–96.CrossRefPubMed

32.

Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE Isoforms Differentially Regulate Brain Amyloid-ß Peptide Clearance. Sci Transl Med. 2011;3:89ra57.CrossRefPubMedPubMedCentral

33.

Yu JT, Tan L, Hardy J. Apolipoprotein E in Alzheimer’s disease: an update. Annu Rev Neurosci. 2014;37:79–100.CrossRefPubMed

34.

Hohsfield LA, Humpel C. Migration of blood cells to beta-amyloid plaques in Alzheimer’s disease. Exp Gerontol. 2015;65:8–15.CrossRefPubMedPubMedCentral

35.

Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, DiNunno N, Rosario AM, Cruz PE, Verbeeck C, Sacino A, Nix S, Janus C, Price ND, Das P, Golde TE. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron. 2015;85:519–33.CrossRefPubMedPubMedCentral

36.

Bales KR, Liu F, Wu S, Lin S, Koger D, DeLong C, Hansen JC, Sullivan PM, Paul SM. Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J Neurosci. 2009;29:6771–79.CrossRefPubMed

37.

Chakrabarty P, Tianbai L, Herring A, Ceballos-Diaz C, Das P, Golde TE. Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol Neurodegener. 2012;7:36.CrossRefPubMedPubMedCentral

38.

D’Andrea MR, Cole GM, Ard MD. The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol Aging. 2004;25:675–83.CrossRefPubMed

39.

Morgan D. The role of microglia in antibody-mediated clearance of amyloid-beta from the brain. CNS Neurol Disord Drug Targets. 2009;8:7–15.CrossRefPubMed

40.

Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K, Braak H. Two types of sporadic cerebral amyloid angiopathy. J Neuropath Exp Neurol. 2002;61:282–93.CrossRefPubMed

41.

Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol. 2003;62:1287–301.CrossRefPubMed

42.

Thal DR, Griffin WS, de Vos RA, Ghebremedhin E. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol. 2008;115:599–609.CrossRefPubMed

43.

Thal DR, Papassotiropoulos A, Saido TC, Griffin WS, Mrak RE, Kolsch H, Del TK, Attems J, Ghebremedhin E. Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer’s disease. Acta Neuropathol. 2010;120:169–83.CrossRefPubMed

44.

Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM, Holtzman DM. Human apolipoprotein E4 alters the amyloid-beta 40: 42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci. 2005;25:2803–10.CrossRefPubMed

45.

Chalmers K, Wilcock GK, Love S. APOE epsilon 4 influences the pathological phenotype of Alzheimer’s disease by favouring cerebrovascular over parenchymal accumulation of A beta protein. Neuropathol Appl Neurobiol. 2003;29:231–38.CrossRefPubMed

46.

Trembath D, Ervin JF, Broom L, Szymanski M, Welsh-Bohmer K, Pieper C, Hulette CM. The distribution of cerebrovascular amyloid in Alzheimer’s disease varies with ApoE genotype. Acta Neuropathol. 2007;113:23–31.CrossRefPubMed

47.

Wisniewski T, Castaño EM, Golabek AA, Vogel T, Frangione B. Acceleration of Alzheimer’s fibril formation by apolipoprotein E in vitro. Am J Pathol. 1994;145:1030–35.PubMedPubMedCentral

48.

Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008;118:4002–13.CrossRefPubMedPubMedCentral

49.

Merlini M, Meyer EP, Ulmann-Schuler A, Nitsch RM. Vascular beta-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAbeta mice. Acta Neuropathol. 2011;122:293–311.CrossRefPubMedPubMedCentral

50.

Klohs J, Baltes C, Princz-Kranz F, Ratering D, Nitsch RM, Knuesel I, Rudin M. Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic ArcAbeta mice. J Neurosci. 2012;32:1705–13.CrossRefPubMed

51.

Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, van der Lugt A, Breteler MM. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke. 2010;41:S103–6.CrossRefPubMed

52.

Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, Krestin GP, Breteler MM. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurol. 2008;70:1208–14.CrossRef

53.

Kovari E, Charidimou A, Herrmann FR, Giannakopoulos P, Bouras C, Gold G. No neuropathological evidence for a direct topographical relation between microbleeds and cerebral amyloid angiopathy. Acta Neuropathol Commun. 2015;3:49.CrossRefPubMedPubMedCentral

54.

Kim M, Bae HJ, Lee J, Kang L, Lee S, Kim S, Lee JE, Lee KM, Yoon BW, Kwon O, Koo JS, Kim BK. APOE epsilon2/epsilon4 polymorphism and cerebral microbleeds on gradient-echo MRI. Neurol. 2005;65:1474–75.CrossRef

55.

McCarron MO, Nicoll JAR, Ironside JW, Love S, Alberts MJ, Bone I. Cerebral amyloid angiopathy-related hemorrhage interaction of APOE epsilon 2 with putative clinical risk factors. Stroke. 1999;30:1643–46.CrossRefPubMed

56.

McCarron MO, Nicoll JAR, Stewart J, Ironside JW, Mann DMA, Love S, Graham DI, Dewar D. The apolipoprotein E epsilon 2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage. J Neuropath Exp Neurol. 1999;58:711–18.CrossRefPubMed

57.

McCarron MO, Nicoll JAR. High frequency of apolipoprotein E epsilon 2 allele is specific for patients with cerebral amyloid angiopathy-related haemorrhage. Neurosci Lett. 1998;247:45–8.CrossRefPubMed

58.

Yates PA, Desmond PM, Phal PM, Steward C, Szoeke C, Salvado O, Ellis KA, Martins RN, Masters CL, Ames D, Villemagne VL, Rowe CC. Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurol. 2014;82:1266–73.CrossRef

59.

Yates PA, Sirisriro R, Villemagne VL, Farquharson S, Masters CL, Rowe CC. Cerebral microhemorrhage and brain beta-amyloid in aging and Alzheimer disease. Neurol. 2011;77:48–54.CrossRef

60.

Song TJ, Kim J, Lee HS, Nam CM, Nam HS, Kim YD, Heo JH. Distribution of cerebral microbleeds determines their association with impaired kidney function. J Clin Neurol. 2014;10:222–28.CrossRefPubMedPubMedCentral

61.

Song TJ, Kim J, Kim YD, Nam HS, Lee HS, Nam CM, Heo JH. The distribution of cerebral microbleeds determines their association with arterial stiffness in non-cardioembolic acute stroke patients. Eur J Neurol. 2014;21:463–69.CrossRefPubMed

62.

Mahley RW, Rall Jr SC. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;1:507–37.CrossRefPubMed

63.

Bales KR, O’Neill SM, Pozdnyakov N, Pan F, Caouette D, Pi Y, Wood KM, Volfson D, Cirrito JR, Han BH, Johnson AW, Zipfel GJ, Samad TA. Passive immunotherapy targeting amyloid-beta reduces cerebral amyloid angiopathy and improves vascular reactivity. Brain. 2016;139:563–77.CrossRefPubMed

64.

Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, Piroozi KS, Jordan WH, Brown DD, Hoffman WP, Holtzman DM, Bales KR, Gitter BD, May PC, Paul SM, DeMattos RB. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005;25:629–36.CrossRefPubMed

65.

Thakker DR, Weatherspoon MR, Harrison J, Keene TE, Lane DS, Kaemmerer WF, Stewart GR, Shafer LL. Intracerebroventricular amyloid-beta antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice. Proc Natl Acad Sci U S A. 2009;106:4501–06.CrossRefPubMedPubMedCentral

Title: APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice
Authors: Joanna E Pankiewicz
Jairo Baquero-Buitrago
Sandrine Sanchez
Jennifer Lopez-Contreras
Jungsu Kim
Patrick M. Sullivan
David M. Holtzman
Martin J. Sadowski
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Molecular Neurodegeneration / Issue 1/2017
Electronic ISSN: 1750-1326
DOI: https://doi.org/10.1186/s13024-017-0156-1

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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