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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 01-06-2015 | Original Article

Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study

Authors: Elena Rodriguez-Vieitez, Ruiqing Ni, Balázs Gulyás, Miklós Tóth, Jenny Häggkvist, Christer Halldin, Larysa Voytenko, Amelia Marutle, Agneta Nordberg

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 7/2015

Abstract

Purpose

Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (Aβ) levels in the brain early in Alzheimer’s disease (AD). The time course and relationships between astrocytosis and Aβ deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis.

Methods

PET imaging with the amyloid plaque tracer ¹¹C-AZD2184 and the astroglial tracer ¹¹C-deuterium-L-deprenyl (¹¹C-DED) was carried out in APPswe mice aged 6, 8–15 and 18–24 months (4–6 animals/group) and in wild-type (wt) mice aged 8–15 and 18–24 months (3–6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for Aβ deposition and astrocytosis by in vitro autoradiography using ³H-AZD2184, ³H-Pittsburgh compound B (PIB) and ³H-L-deprenyl and immunostaining performed with antibodies for Aβ₄₂ and glial fibrillary acidic protein (GFAP) in sagittal brain sections.

Results

¹¹C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18–24 months than in age-matched wt mice. Cortical and hippocampal ¹¹C-DED PET binding was significantly higher at 6 months than at 8–15 months or 18–24 months in APPswe mice, and it was also higher than at 8–15 months in wt mice. In vitro autoradiography ³H-AZD2184 and ³H-PIB binding confirmed the in vivo findings with ¹¹C-AZD2184 and demonstrated age-dependent increases in Aβ deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in ³H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more Aβ₄₂ deposits in the cortex and hippocampus and more GFAP⁺ reactive astrocytes in the hippocampus at 18–24 months than at 6 months in APPswe mice.

Conclusion

The findings provide further in vivo evidence that astrocytosis occurs early in AD, preceding Aβ plaque deposition.

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Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297(5580):353–6. doi:10.1126/science.1072994.CrossRefPubMed

Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature 2004;430(7000):631–9. doi:10.1038/nature02621.CrossRefPubMedCentralPubMed

Nordberg A. Amyloid imaging in early detection of Alzheimer’s disease. Neurodegener Dis 2010;7(1–3):136–8. doi:10.1159/000289223.

Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55(3):306–19.CrossRefPubMed

Kudo Y, Okamura N, Furumoto S, Tashiro M, Furukawa K, Maruyama M, et al. 2-(2-[2-Dimethylaminothiazol-5-yl]ethenyl)-6- (2-[fluoro]ethoxy)benzoxazole: a novel PET agent for in vivo detection of dense amyloid plaques in Alzheimer’s disease patients. J Nucl Med 2007;48(4):553–61.CrossRefPubMed

Nyberg S, Jönhagen ME, Cselényi Z, Halldin C, Julin P, Olsson H, et al. Detection of amyloid in Alzheimer’s disease with positron emission tomography using [11C]AZD2184. Eur J Nucl Med Mol Imaging 2009;36(11):1859–63. doi:10.1007/s00259-009-1182-1.CrossRefPubMedCentralPubMed

Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 2002;10(1):24–35.CrossRefPubMed

Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011;305(3):275–83. doi:10.1001/jama.2010.2008.CrossRefPubMed

Nelissen N, Van Laere K, Thurfjell L, Owenius R, Vandenbulcke M, Koole M, et al. Phase 1 study of the Pittsburgh compound B derivative 18F-flutemetamol in healthy volunteers and patients with probable Alzheimer disease. J Nucl Med 2009;50(8):1251–9. doi:10.2967/jnumed.109.063305.CrossRefPubMed

10.

Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O’Keefe G, et al. Imaging of amyloid beta in Alzheimer’s disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol 2008;7(2):129–35. doi:10.1016/S1474-4422(08)70001-2.CrossRefPubMed

11.

Cselényi Z, Jönhagen ME, Forsberg A, Halldin C, Julin P, Schou M, et al. Clinical validation of 18F-AZD4694, an amyloid-β-specific PET radioligand. J Nucl Med 2012;53(3):415–24. doi:10.2967/jnumed.111.094029.CrossRefPubMed

12.

Ni R, Gillberg PG, Bergfors A, Marutle A, Nordberg A. Amyloid tracers detect multiple binding sites in Alzheimer’s disease brain tissue. Brain 2013;136(Pt 7):2217–27. doi:10.1093/brain/awt142.CrossRefPubMed

13.

Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 2013;12(4):357–67. doi:10.1016/S1474-4422(13)70044-9.CrossRefPubMed

14.

McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995;21(2):195–218.CrossRefPubMed

15.

Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000;21(3):383–421.CrossRefPubMedCentralPubMed

16.

Pekny M, Wilhelmsson U, Pekna M. The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 2014;565:30–8. doi:10.1016/j.neulet.2013.12.071.CrossRefPubMed

17.

Verkhratsky A, Marutle A, Rodríguez-Arellano JJ, Nordberg A. Glial asthenia and functional paralysis: a new perspective on neurodegeneration and Alzheimer’s disease. Neuroscientist 2014. doi:10.1177/1073858414547132.

18.

Carter SF, Schöll M, Almkvist O, Wall A, Engler H, Långström B, et al. Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 2012;53(1):37–46. doi:10.2967/jnumed.110.087031.CrossRefPubMed

19.

Ashe KH, Zahs KR. Probing the biology of Alzheimer’s disease in mice. Neuron 2010;66(5):631–45. doi:10.1016/j.neuron.2010.04.031.CrossRefPubMedCentralPubMed

20.

Mustafiz T, Portelius E, Gustavsson MK, Hölttä M, Zetterberg H, Blennow K, et al. Characterization of the brain β-amyloid isoform pattern at different ages of Tg2576 mice. Neurodegener Dis 2011;8(5):352–63.CrossRefPubMed

21.

Nagy K, Tóth M, Major P, Patay G, Egri G, Häggkvist J, et al. Performance evaluation of the small-animal nanoScan PET/MRI system. J Nucl Med 2013;54(10):1825–32. doi:10.2967/jnumed.112.119065.CrossRefPubMed

22.

Szanda I, Mackewn J, Patay G, Major P, Sunassee K, Mullen GE, et al. National Electrical Manufacturers Association NU-4 performance evaluation of the PET component of the NanoPET/CT preclinical PET/CT scanner. J Nucl Med 2011;52(11):1741–7. doi:10.2967/jnumed.111.088260.CrossRefPubMed

23.

Andersson JD, Varnäs K, Cselényi Z, Gulyás B, Wensbo D, Finnema SJ, et al. Radiosynthesis of the candidate beta-amyloid radioligand [(11)C]AZD2184: positron emission tomography examination and metabolite analysis in cynomolgus monkeys. Synapse 2010;64(10):733–41. doi:10.1002/syn.20782.CrossRefPubMed

24.

Gulyás B, Pavlova E, Kása P, Gulya K, Bakota L, Várszegi S, et al. Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-L-deprenyl using whole hemisphere autoradiography. Neurochem Int 2011;58(1):60–8. doi:10.1016/j.neuint.2010.10.013.CrossRefPubMed

25.

Johnson AE, Jeppsson F, Sandell J, Wensbo D, Neelissen JA, Juréus A, et al. AZD2184: a radioligand for sensitive detection of beta-amyloid deposits. J Neurochem 2009;108(5):1177–86. doi:10.1111/j.1471-4159.2008.05861.x.CrossRefPubMed

26.

Marutle A, Gillberg PG, Bergfors A, Yu W, Ni R, Nennesmo I, et al. 3H-Deprenyl and 3H-PIB autoradiography show different laminar distributions of astroglia and fibrillar β-amyloid in Alzheimer brain. J Neuroinflammation 2013;10(1):90. doi:10.1186/1742-2094-10-90.CrossRefPubMedCentralPubMed

27.

Zimmer ER, Parent MJ, Cuello AC, Gauthier S, Rosa-Neto P. MicroPET imaging and transgenic models: a blueprint for Alzheimer’s disease clinical research. Trends Neurosci 2014;37(11):629–41. doi:10.1016/j.tins.2014.07.002.CrossRefPubMed

28.

Klunk WE, Lopresti BJ, Ikonomovic MD, Lefterov IM, Koldamova RP, Abrahamson EE, et al. Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer’s disease brain but not in transgenic mouse brain. J Neurosci 2005;25(46):10598–606. doi:10.1523/JNEUROSCI.2990-05.2005.

29.

Maeda J, Zhang MR, Okauchi T, Ji B, Ono M, Hattori S, et al. In vivo positron emission tomographic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer’s disease and related disorders. J Neurosci 2011;31(12):4720–30. doi:10.1523/JNEUROSCI.3076-10.2011.CrossRefPubMedCentralPubMed

30.

Snellman A, López-Picón FR, Rokka J, Salmona M, Forloni G, Scheinin M, et al. Longitudinal amyloid imaging in mouse brain with 11C-PIB: comparison of APP23, Tg2576, and APPswe-PS1dE9 mouse models of Alzheimer disease. J Nucl Med 2013;54(8):1434–41. doi:10.2967/jnumed.112.110163.CrossRefPubMed

31.

Toyama H, Ye D, Ichise M, Liow JS, Cai L, Jacobowitz D, et al. PET imaging of brain with the beta-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer’s disease. Eur J Nucl Med Mol Imaging 2005;32(5):593–600. doi:10.1007/s00259-005-1780-5.CrossRefPubMed

32.

Manook A, Yousefi BH, Willuweit A, Platzer S, Reder S, Voss A, et al. Small-animal PET imaging of amyloid-beta plaques with [11C]PiB and its multi-modal validation in an APP/PS1 mouse model of Alzheimer’s disease. PLoS One 2012;7(3):e31310. doi:10.1371/journal.pone.0031310.CrossRefPubMedCentralPubMed

33.

Rominger A, Brendel M, Burgold S, Keppler K, Baumann K, Xiong G, et al. Longitudinal assessment of cerebral β-amyloid deposition in mice overexpressing Swedish mutant β-amyloid precursor protein using 18F-florbetaben PET. J Nucl Med 2013;54(7):1127–34. doi:10.2967/jnumed.112.114660.CrossRefPubMed

34.

Poisnel G, Dhilly M, Moustié O, Delamare J, Abbas A, Guilloteau D, et al. PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition. Neurobiol Aging 2012;33(11):2561–71. doi:10.1016/j.neurobiolaging.2011.12.024.CrossRefPubMed

35.

Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG. Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 2001;21(2):372–81.PubMed

36.

Zhang Y, Barres BA. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol 2010;20(5):588–94. doi:10.1016/j.conb.2010.06.005.CrossRefPubMed

37.

Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 2014;81(2):229–48. doi:10.1016/j.neuron.2013.12.034.CrossRefPubMedCentralPubMed

38.

Yeh CY, Vadhwana B, Verkhratsky A, Rodríguez JJ. Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer’s disease. ASN Neuro 2011;3(5):271–9. doi:10.1042/AN20110025.CrossRefPubMed

39.

Kulijewicz-Nawrot M, Verkhratsky A, Chvátal A, Syková E, Rodríguez JJ. Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. J Anat 2012;221(3):252–62. doi:10.1111/j.1469-7580.2012.01536.x.CrossRefPubMedCentralPubMed

40.

Beauquis J, Vinuesa A, Pomilio C, Pavía P, Galván V, Saravia F. Neuronal and glial alterations, increased anxiety, and cognitive impairment before hippocampal amyloid deposition in PDAPP mice, model of Alzheimer’s disease. Hippocampus 2014;24(3):257–69. doi:10.1002/hipo.22219.CrossRefPubMed

41.

Olabarria M, Noristani HN, Verkhratsky A, Rodríguez JJ. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 2010;58(7):831–8. doi:10.1002/glia.20967.PubMed

42.

Allaman I, Gavillet M, Bélanger M, Laroche T, Viertl D, Lashuel HA, et al. Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci 2010;30(9):3326–38. doi:10.1523/JNEUROSCI.5098-09.2010.

43.

Serrano-Pozo A, Gómez-Isla T, Growdon JH, Frosch MP, Hyman BT. A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 2013;182(6):2332–44. doi:10.1016/j.ajpath.2013.02.031.CrossRefPubMedCentralPubMed

44.

Jossan SS, Gillberg PG, d’Argy R, Aquilonius SM, Långström B, Halldin C, et al. Quantitative localization of human brain monoamine oxidase B by large section autoradiography using L-[3H]deprenyl. Brain Res 1991;547(1):69–76.CrossRefPubMed

45.

Kadir A, Marutle A, Gonzalez D, Schöll M, Almkvist O, Mousavi M, et al. Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease. Brain 2011;134(Pt 1):301–17. doi:10.1093/brain/awq349.CrossRefPubMedCentralPubMed

46.

Fowler JS, MacGregor RR, Wolf AP, Arnett CD, Dewey SL, Schlyer D, et al. Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET. Science 1987;235(4787):481–5.CrossRefPubMed

47.

Choo IH, Carter SF, Schöll ML, Nordberg A. Astrocytosis measured by (11)C-deprenyl PET correlates with decrease in gray matter density in the parahippocampus of prodromal Alzheimer’s patients. Eur J Nucl Med Mol Imaging 2014;41(11):2120–6. doi:10.1007/s00259-014-2859-7.CrossRefPubMed

48.

Nordberg A. Molecular imaging in sporadic Alzheimer’s disease populations and those genetically at risk. Neurodegener Dis 2014;13(2–3):160–2. doi:10.1159/000356333.CrossRefPubMed

49.

Anderson MA, Ao Y, Sofroniew MV. Heterogeneity of reactive astrocytes. Neurosci Lett 2014;565:23–9. doi:10.1016/j.neulet.2013.12.030.CrossRefPubMed

50.

Kamphuis W, Middeldorp J, Kooijman L, Sluijs JA, Kooi EJ, Moeton M, et al. Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer’s disease. Neurobiol Aging 2014;35(3):492–510. doi:10.1016/j.neurobiolaging.2013.09.035.CrossRefPubMed

51.

Kamphuis W, Mamber C, Moeton M, Kooijman L, Sluijs JA, Jansen AH, et al. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One 2012;7(8):e42823. doi:10.1371/journal.pone.0042823.CrossRefPubMedCentralPubMed

52.

Rodríguez JJ, Yeh CY, Terzieva S, Olabarria M, Kulijewicz-Nawrot M, Verkhratsky A. Complex and region-specific changes in astroglial markers in the aging brain. Neurobiol Aging 2014;35(1):15–23. doi:10.1016/j.neurobiolaging.2013.07.002.CrossRefPubMed

53.

Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2005;2:22. doi:10.1186/1742-2094-2-22.CrossRefPubMedCentralPubMed

54.

DaRocha-Souto B, Scotton TC, Coma M, Serrano-Pozo A, Hashimoto T, Serenó L, et al. Brain oligomeric β-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice. J Neuropathol Exp Neurol 2011;70(5):360–76. doi:10.1097/Nen.0b013e318217a118.CrossRefPubMedCentralPubMed

55.

Kraft AW, Hu X, Yoon H, Yan P, Xiao Q, Wang Y, et al. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J 2013;27(1):187–98. doi:10.1096/fj.12-208660.CrossRefPubMedCentralPubMed

56.

Unger C, Hedberg MM, Mustafiz T, Svedberg MM, Nordberg A. Early changes in Abeta levels in the brain of APPswe transgenic mice–implication on synaptic density, alpha7 neuronal nicotinic acetylcholine- and N-methyl-D-aspartate receptor levels. Mol Cell Neurosci 2005;30(2):218–27. doi:10.1016/j.mcn.2005.07.012.CrossRefPubMed

57.

Song W, Zhou LJ, Zheng SX, Zhu XZ. Amyloid-beta 25-35 peptide induces expression of monoamine oxidase B in cultured rat astrocytes. Acta Pharmacol Sin 2000;21(6):557–63.PubMed

58.

Miller G. Neuroscience. The dark side of glia. Science 2005;308(5723):778–81. doi:10.1126/science.308.5723.778.CrossRefPubMed

59.

Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et al. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 2003;9(4):453–7. doi:10.1038/nm838.CrossRefPubMed

60.

Thal DR. The role of astrocytes in amyloid β-protein toxicity and clearance. Exp Neurol 2012;236(1):1–5. doi:10.1016/j.expneurol.2012.04.021.CrossRefPubMed

Title: Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study
Authors: Elena Rodriguez-Vieitez
Ruiqing Ni
Balázs Gulyás
Miklós Tóth
Jenny Häggkvist
Christer Halldin
Larysa Voytenko
Amelia Marutle
Agneta Nordberg
Publication date: 01-06-2015
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 7/2015
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-015-3047-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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