Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition

Journal of Neuroinflammation

G William Rebeck¹  Mary Jo LaDu²  Leon M Tai²  Gustavo A Rodriguez¹ 

[1] Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road, NW Washington, DC 20057, USA;Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA

关键词: MOAB2;    APOE4;    Aβ_1–42;    Alzheimer’s disease;    Microglia;    Neuroinflammation;   

Others  :  803466
DOI  :  10.1186/1742-2094-11-111

 received in 2014-03-13, accepted in 2014-05-29,  发布年份 2014

【 摘 要 】

Background

Having the apolipoprotein E4 (APOE-ϵ4) allele is the strongest genetic risk factor for the development of Alzheimer’s disease (AD). Accumulation of amyloid beta (Aβ) in the brain is influenced by APOE genotype. Transgenic mice co-expressing five familial AD mutations (5xFAD) in the presence of human APOE alleles (ϵ2, ϵ3 or ϵ4) exhibit APOE genotype-specific differences in early Aβ accumulation, suggesting an interaction between APOE and AD pathology. Whether APOE genotype affects Aβ-plaque-associated neuroinflammation remains unclear. In the current study, we address the role of APOE genotype on Aβ-associated microglial reactivity in the EFAD transgenic mouse model.

Methods

We analyzed Aβ-induced glial activation in the brains of 6-month-old EFAD transgenic mice (E2FAD, E3FAD and E4FAD). Region-specific morphological profiles of Aβ plaques in EFAD brain sections were compared using immunofluorescence staining. We then determined the degree of glial activation in sites of Aβ deposition while comparing levels of the inflammatory cytokine Interleukin-1β (IL-1β) by ELISA. Finally, we quantified parameters of Aβ-associated microglial reactivity using double-stained EFAD brain sections.

Results

Characterization of Aβ plaques revealed there were larger and more intensely stained plaques in E4FAD mice relative to E2FAD and E3FAD mice. E4FAD mice also had a greater percentage of compact plaques in the subiculum than E3FAD mice. Reactive microglia and dystrophic astrocytes were prominent in EFAD brains, and primarily localized to two sites of significant Aβ deposition: the subiculum and deep layers of the cortex. Cortical levels of IL-1β were nearly twofold greater in E4FAD mice relative to E3FAD mice. To control for differences in levels of Aβ in the different EFAD mice, we analyzed the microglia within domains of specific Aβ deposits. Morphometric analyses revealed increased measures of microglial reactivity in E4FAD mice, including greater dystrophy, increased fluorescence intensity and a higher density of reactive cells surrounding cortical plaques, than in E3FAD mice.

Conclusions

In addition to altering morphological profiles of Aβ deposition, APOE genotype influences Aβ-induced glial activation in the adult EFAD cortex. These data support a role for APOE in modulating Aβ-induced neuroinflammatory responses in AD progression, and support the use of EFAD mice as a suitable model for mechanistic studies of Aβ-associated neuroinflammation.

【 授权许可】

   
2014 Rodriguez et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Selkoe DJ: Resolving controversies on the path to Alzheimer's therapeutics. Nat Med 2011, 17:1060-1065.
• [2]Selkoe DJ: Alzheimer's disease. Cold Spring Harb Perspect Biol 2011, 3(7):1-16.
• [3]Braak H, Braak E: Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging 1995, 16:271-278. discussion 278–284
• [4]Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002, 297:353-356.
• [5]Amor S, Puentes F, Baker D, van der Valk P: Inflammation in neurodegenerative diseases. Immunology 2010, 129:154-169.
• [6]Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D: Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 1989, 24:173-182.
• [7]Matsuoka Y, Picciano M, La Francois J, Duff K: Fibrillar beta-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer's disease. Neuroscience 2001, 104:609-613.
• [8]Cotter RL, Burke WJ, Thomas VS, Potter JF, Zheng J, Gendelman HE: Insights into the neurodegenerative process of Alzheimer's disease: a role for mononuclear phagocyte-associated inflammation and neurotoxicity. J Leukoc Biol 1999, 65:416-427.
• [9]Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, De Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT: Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 2008, 451:720-724.
• [10]Zannis VI, Breslow JL, Utermann G, Mahley RW, Weisgraber KH, Havel RJ, Goldstein JL, Brown MS, Schonfeld G, Hazzard WR, Blum C: Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res 1982, 23:911-914.
• [11]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-beta peptide clearance. Sci Transl Med 2011, 3(89):1-11.
• [12]Grimmer T, Tholen S, Yousefi BH, Alexopoulos P, Forschler A, Forstl H, Henriksen G, Klunk WE, Mathis CA, Perneczky R, Sorg C, Kurz A, Drzezga A: Progression of cerebral amyloid load is associated with the apolipoprotein E ϵ4 genotype in Alzheimer's disease. Biol Psychiatry 2010, 68:879-884.
• [13]Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, Mitani A, Joyner D, Thyssen DH, Bacskai BJ, Frosch MP, Spires-Jones TL, Finn MB, Holtzman DM, Hyman BT: Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid beta peptide. J Neurosci 2012, 32:15181-15192.
• [14]Irizarry MC, Cheung BS, Rebeck GW, Paul SM, Bales KR, Hyman BT: Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid beta-peptide deposition in homozygous APP(V717F) transgenic mice. Acta Neuropathol 2000, 100:451-458.
• [15]Rebeck GW, Reiter JS, Strickland DK, Hyman BT: Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron 1993, 11:575-580.
• [16]Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Mathis CA, Price JC, Aizenstein HJ, DeKosky ST, Caselli RJ: Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A 2009, 106:6820-6825.
• [17]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, 90:9649-9653.
• [18]Tai LM, Youmans KL, Jungbauer L, Yu C, Ladu MJ: Introducing human APOE into abeta transgenic mouse models. Int J Alzheimers Dis 2011, 2011:810981.
• [19]Tiraboschi P, Hansen LA, Masliah E, Alford M, Thal LJ, Corey-Bloom J: Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 2004, 62:1977-1983.
• [20]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, 29:6771-6779.
• [21]Drzezga A, Grimmer T, Henriksen G, Muhlau M, Perneczky R, Miederer I, Praus C, Sorg C, Wohlschlager A, Riemenschneider M, Wester HJ, Foerstl H, Schwaiger M, Kurz A: Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology 2009, 72:1487-1494.
• [22]Kim J, Basak JM, Holtzman DM: The role of apolipoprotein E in Alzheimer's disease. Neuron 2009, 63:287-303.
• [23]Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993, 261:921-923.
• [24]Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD: Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 1993, 43:1467-1472.
• [25]Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD: Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993, 90:1977-1981.
• [26]Colton CA, Needham LK, Brown C, Cook D, Rasheed K, Burke JR, Strittmatter WJ, Schmechel DE, Vitek MP: APOE genotype-specific differences in human and mouse macrophage nitric oxide production. J Neuroimmunol 2004, 147:62-67.
• [27]Lynch JR, Tang W, Wang H, Vitek MP, Bennett ER, Sullivan PM, Warner DS, Laskowitz DT: APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem 2003, 278:48529-48533.
• [28]Mayeux R, Ottman R, Maestre G, Ngai C, Tang MX, Ginsberg H, Chun M, Tycko B, Shelanski M: Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease. Neurology 1995, 45:555-557.
• [29]Ponsford J, McLaren A, Schonberger M, Burke R, Rudzki D, Olver J, Ponsford M: The association between apolipoprotein E and traumatic brain injury severity and functional outcome in a rehabilitation sample. J Neurotrauma 2011, 28:1683-1692.
• [30]Zhu Y, Nwabuisi-Heath E, Dumanis SB, Tai LM, Yu C, Rebeck GW, LaDu MJ: APOE genotype alters glial activation and loss of synaptic markers in mice. Glia 2012, 60:559-569.
• [31]Tai LM, Bilousova T, Jungbauer L, Roeske SK, Youmans KL, Yu C, Poon WW, Cornwell LB, Miller CA, Vinters HV, Van Eldik LJ, Fardo DW, Estus S, Bu G, Gylys KH, LaDu MJ: Levels of soluble apolipoprotein E/amyloid-beta (Abeta) complex are reduced and oligomeric Abeta increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J Biol Chem 2013, 288:5914-5926.
• [32]Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, Kim J, Eimer WA, Estus S, Rebeck GW, Bu G, Yu C, LaDu MJ: APOE4-specific changes in Aβ accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem 2012, 287:41774-41786.
• [33]Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R: Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 2006, 26:10129-10140.
• [34]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, 272:17972-17980.
• [35]Paxinos G, Franklin KBJ: The Mouse Brain in Stereotaxic Coordinates. 2nd edition. San Diego: Academic; 2001.
• [36]Youmans KL, Tai LM, Kanekiyo T, Stine WB Jr, Michon SC, Nwabuisi-Heath E, Manelli AM, Fu Y, Riordan S, Eimer WA, Binder L, Bu G, Yu C, Hartley DM, LaDu MJ: Intraneuronal Abeta detection in 5xFAD mice by a new Abeta-specific antibody. Mol Neurodegener 2012, 7:8.
• [37]Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A: Fiji: an open-source platform for biological-image analysis. Nat Methods 2012, 9:676-682.
• [38]Katsouri L, Georgopoulos S: Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model. PLoS One 2011, 6:e21880.
• [39]Burda JE, Sofroniew MV: Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 2014, 81:229-248.
• [40]Birch AM, Katsouri L, Sastre M: Modulation of inflammation in transgenic models of Alzheimer's disease. J Neuroinflammation 2014, 11:25.
• [41]Hillmann A, Hahn S, Schilling S, Hoffmann T, Demuth HU, Bulic B, Schneider-Axmann T, Bayer TA, Weggen S, Wirths O: No improvement after chronic ibuprofen treatment in the 5XFAD mouse model of Alzheimer's disease. Neurobiol Aging 2012, 33:e839-e850.
• [42]Wolf AB, Valla J, Bu G, Kim J, Ladu MJ, Reiman EM, Caselli RJ: Apolipoprotein E as a beta-amyloid-independent factor in Alzheimer's disease. Alzheimers Res Ther 2013, 5:38.
• [43]Laskowitz DT, Song P, Wang H, Mace B, Sullivan PM, Vitek MP, Dawson HN: Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic. J Neurotrauma 2010, 27:1983-1995.
• [44]Prokop S, Miller KR, Heppner FL: Microglia actions in Alzheimer's disease. Acta Neuropathol 2013, 126:461-477.
• [45]Tambuyzer BR, Ponsaerts P, Nouwen EJ: Microglia: gatekeepers of central nervous system immunology. J Leukoc Biol 2009, 85:352-370.
• [46]McGeer PL, Itagaki S, Tago H, McGeer EG: Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987, 79:195-200.
• [47]El Khoury J, Luster AD: Mechanisms of microglia accumulation in Alzheimer's disease: therapeutic implications. Trends Pharmacol Sci 2008, 29:626-632.
• [48]El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, Freeman MW, Luster AD: CD36 mediates the innate host response to beta-amyloid. J Exp Med 2003, 197:1657-1666.
• [49]Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, Rossi F: Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 1995, 374:647-650.
• [50]Barger SW, Harmon AD: Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 1997, 388:878-881.
• [51]Laskowitz DT, Goel S, Bennett ER, Matthew WD: Apolipoprotein E suppresses glial cell secretion of TNF alpha. J Neuroimmunol 1997, 76:70-74.
• [52]Pocivavsek A, Burns MP, Rebeck GW: Low-density lipoprotein receptors regulate microglial inflammation through c-Jun N-terminal kinase. Glia 2009, 57:444-453.
• [53]Pocivavsek A, Mikhailenko I, Strickland DK, Rebeck GW: Microglial low-density lipoprotein receptor-related protein 1 modulates c-Jun N-terminal kinase activation. J Neuroimmunol 2009, 214:25-32.
• [54]Fagan AM, Murphy BA, Patel SN, Kilbridge JF, Mobley WC, Bu G, Holtzman DM: Evidence for normal aging of the septo-hippocampal cholinergic system in apoE (-/-) mice but impaired clearance of axonal degeneration products following injury. Exp Neurol 1998, 151:314-325.
• [55]Lomnitski L, Nyska A, Shohami E, Chen Y, Michaelson DM: Increased levels of intracellular iron in the brains of ApoE-deficient mice with closed head injury. Exp Toxicol Pathol 2000, 52:177-183.
• [56]Riddell DR, Zhou H, Atchison K, Warwick HK, Atkinson PJ, Jefferson J, Xu L, Aschmies S, Kirksey Y, Hu Y, Wagner E, Parratt A, Xu J, Li Z, Zaleska MM, Jacobsen JS, Pangalos MN, Reinhart PH: Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J Neurosci 2008, 28:11445-11453.
• [57]Sullivan PM, Han B, Liu F, Mace BE, Ervin JF, Wu S, Koger D, Paul S, Bales KR: Reduced levels of human apoE4 protein in an animal model of cognitive impairment. Neurobiol Aging 2011, 32:791-801.
• [58]Vitek MP, Brown CM, Colton CA: APOE genotype-specific differences in the innate immune response. Neurobiol Aging 2009, 30:1350-1360.
• [59]Lee CY, Tse W, Smith JD, Landreth GE: Apolipoprotein E promotes beta-amyloid trafficking and degradation by modulating microglial cholesterol levels. J Biol Chem 2012, 287:2032-2044.
• [60]Keene CD, Cudaback E, Li X, Montine KS, Montine TJ: Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer's disease. Curr Opin Neurobiol 2011, 21:920-928.
• [61]Tai LM, Mehra S, Shete V, Estus S, Rebeck GW, Bu G, Ladu MJ: Soluble apoE/Abeta complex: mechanism and therapeutic target for APOE4-induced AD risk. Mol Neurodegener 2014, 9:2.
• [62]Hong S, Quintero-Monzon O, Ostaszewski BL, Podlisny DR, Cavanaugh WT, Yang T, Holtzman DM, Cirrito JR, Selkoe DJ: Dynamic analysis of amyloid beta-protein in behaving mice reveals opposing changes in ISF versus parenchymal Abeta during age-related plaque formation. J Neurosci 2011, 31:15861-15869.
• [63]Koffie RM, Hashimoto T, Tai HC, Kay KR, Serrano-Pozo A, Joyner D, Hou S, Kopeikina KJ, Frosch MP, Lee VM, Holtzman DM, Hyman BT, Spires-Jones TL: Apolipoprotein E4 effects in Alzheimer's disease are mediated by synaptotoxic oligomeric amyloid-beta. Brain 2012, 135:2155-2168.