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

• Published in: European journal of nuclear medicine and molecular imaging Vol. 42; no. 7; pp. 1119 - 1132
• Main Authors: Rodriguez-Vieitez, Elena, Ni, Ruiqing, Gulyás, Balázs, Tóth, Miklós, Häggkvist, Jenny, Halldin, Christer, Voytenko, Larysa, Marutle, Amelia, Nordberg, Agneta
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2015; Springer Nature B.V
• Subjects: Alzheimer Disease - diagnostic imaging; Alzheimer Disease - pathology; Alzheimer's disease; Aminopyridines - pharmacokinetics; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animals; Benzothiazoles - pharmacokinetics; Brain - diagnostic imaging; Brain - metabolism; Brain - pathology; Carbon Radioisotopes - pharmacokinetics; Cardiology; Female; Gliosis - diagnostic imaging; Gliosis - pathology; Imaging; Immunohistochemistry; Male; Medical imaging; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Mutation; Nuclear Medicine; Oncology; Original Article; Orthopedics; Plaque, Amyloid - diagnostic imaging; Plaque, Amyloid - pathology; Positron-Emission Tomography; Protein Binding; Radiology; Radiopharmaceuticals - pharmacokinetics; Tomography; C-AZD2184; deprenyl; Alzheimer’s disease; PET imaging; Astrocytosis; Amyloid; APPswe mice; C-Deuterium
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-015-3047-0

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 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 Aβ 42 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 Aβ 42 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.