title: Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study.
abstract: OBJECTIVE
  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 (11)C-AZD2184 and the astroglial tracer (11)C-deuterium-L-deprenyl ((11)C-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 (3)H-AZD2184, (3)H-Pittsburgh compound B (PIB) and (3)H-L-deprenyl and immunostaining performed with antibodies for Aβ42 and glial fibrillary acidic protein (GFAP) in sagittal brain sections.
  
  
  RESULTS
  (11)C-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 (11)C-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 (3)H-AZD2184 and (3)H-PIB binding confirmed the in vivo findings with (11)C-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 (3)H-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.
  
  
  CONCLUSIONS
  The findings provide further in vivo evidence that astrocytosis occurs early in AD, preceding Aβ plaque deposition.
authors.affiliation: Division of Translational Alzheimer Neurobiology, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum 5th Floor, Blickagången 6, 141 57, Stockholm, Sweden.
authors.forename: Elena
authors.initials: E
authors.lastname: Rodriguez-Vieitez
authors.forename: Ruiqing
authors.initials: R
authors.lastname: Ni
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.forename: Jenny
authors.initials: J
authors.lastname: Häggkvist
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Larysa
authors.initials: L
authors.lastname: Voytenko
authors.forename: Amelia
authors.initials: A
authors.lastname: Marutle
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000473:pathology; D000631:Aminopyridines / Q000493:pharmacokinetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D005260:Female; D005911:Gliosis / Q000000981:diagnostic imaging* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000473:pathology; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics
chemical_list: C539976:2-(6-(methylamino)pyridin-3-yl)-1,3-benzothiazol-6-ol; D000631:Aminopyridines; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals