Journal
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
Volume 42, Issue 7, Pages 1119-1132Publisher
SPRINGER
DOI: 10.1007/s00259-015-3047-0
Keywords
Alzheimer's disease; APPswe mice; Amyloid; Astrocytosis; C-11-AZD2184; C-11-Deuterium-L-deprenyl; PET imaging
Funding
- Swedish Research Council [05817]
- Karolinska Institutet Strategic Neuroscience program
- Stockholm County Council-Karolinska Institutet
- Swedish Brain Power
- Swedish Brain Foundation
- Alzheimer Foundation in Sweden
- Dementia Association (Demensfonden)
- Knut and Alice Wallenberg Foundation
- EU
- Foundation for Old Servants
- Karolinska Institutet's Foundation for Aging Research
- Gun and Bertil Stohne's Foundation
- Sigurd and Elsa Golje's Foundation
- Loo and Hans Osterman's Foundation
- Lars Hierta Memorial Foundation
- Ragnhild and Einar Lundstrom's Memorial Foundation
- Olle Engkvist Byggmastare Foundation
- Ahlen Foundation
- Magnus Bergvall's Foundation
- Wenner-Gren Foundation
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Purpose Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (A beta) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and A beta 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 C-11-AZD2184 and the astroglial tracer C-11-deuterium-L-deprenyl (C-11-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 A beta deposition and astrocytosis by in vitro autoradiography using H-3-AZD2184, H-3-Pittsburgh compound B (PIB) and H-3-L-deprenyl and immunostaining performed with antibodies for A beta(42) and glial fibrillary acidic protein (GFAP) in sagittal brain sections. Results C-11-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 C-11-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 H-3-AZD2184 and H-3-PIB binding confirmed the in vivo findings with C-11-AZD2184 and demonstrated age-dependent increases in A beta deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in H-3-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more A beta(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 A beta plaque deposition.
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