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

Abstract

PurposePathological 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.MethodsPET 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.Results11C-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.ConclusionThe findings provide further in vivo evidence that astrocytosis occurs early in AD, preceding Aβ plaque deposition.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-015-3047-0) contains supplementary material, which is available to authorized users.

Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease

“…In fact, the major increase in Aβ deposition was found between 8 and 12 months, while MAO-B levels appeared to be elevated already at 8 months. These results are also in line with a previous study that reported elevated [ 11 C]DED binding in APP swe mice compared with WT mice [30]. Somewhat contradictory to the present study, this previous study showed higher [ 11 C]DED binding in young 6-month-old APP swe mice compared with older mice.…”

“…The biochemical quantification of GFAP with ELISA confirmed the results obtained with immunohistochemistry and indicated that increased GFAP levels were a consequence of, or at least mirrored, the Aβ accumulation. These results are also supported by the previous studies in APP swe mice and on post mortem human brain tissue [30,42]. Another preclinical study, conducted in APP/PS1 mice, focusing on GABA function reported low degree of co- localization of MAO-B and GFAP [43].…”

“…Somewhat contradictory to the present study, this previous study showed higher [ 11 C]DED binding in young 6-month-old APP swe mice compared with older mice. This decline in [ 11 C]DED binding between 6-month-old APP swe mice and older mice could, however, not be confirmed by in vitro autoradiography [30]. One limitation of the present [ 11 C]DED data is the low number of animals in each group, and that animals younger than 8 months were not investigated with PET.…”

“…Based on recent studies with [ 11 C]DED PET imaging of astrogliosis it has been suggested that astrogliosis occurs early in AD and precedes the occurrence of insoluble plaques [30], while other studies have found an increase of astrogliosis in parallel with the progression in Braak stages [31]. The aim of this study was to investigate how in vivo quantification of astrogliosis using PET radioligand [ 11 C]DED corresponds to the amount of reactive astrocytes found in different brain regions using GFAP and vimentin immunohistochemistry, and GFAP ELISA in isolated brain tissue from young and old APP ArcSwe and wild-type control (WT) mice.…”

Glial Activation and Glucose Metabolism in a Transgenic Amyloid Mouse Model: A Triple-Tracer PET Study

“…In particular, small-animal PET imaging of b-amyloid has been successfully established in the past few years (9,10). However, information regarding neuroinflammation in these models remains sparse and rather inconsistent (11)(12)(13).…”