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Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study.
Eur J Nucl Med Mol Imaging. 2015 Jun; 42(7):1119-32.EJ

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 (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.

CONCLUSION

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

Links

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Authors+Show Affiliations

Rodriguez-Vieitez E
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.
Ni R
No affiliation info available
Gulyás B
No affiliation info available
Tóth M
No affiliation info available
Häggkvist J
No affiliation info available
Halldin C
No affiliation info available
Voytenko L
No affiliation info available
Marutle A
No affiliation info available
Nordberg A
No affiliation info available

MeSH

Alzheimer DiseaseAminopyridinesAmyloid beta-PeptidesAnimalsBenzothiazolesBrainCarbon RadioisotopesFemaleGliosisMaleMiceMice, TransgenicMutationPlaque, AmyloidPositron-Emission TomographyProtein BindingRadiopharmaceuticals

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25893384

Citation

Rodriguez-Vieitez, Elena, et al. "Astrocytosis Precedes Amyloid Plaque Deposition in Alzheimer APPswe Transgenic Mouse Brain: a Correlative Positron Emission Tomography and in Vitro Imaging Study." European Journal of Nuclear Medicine and Molecular Imaging, vol. 42, no. 7, 2015, pp. 1119-32.
Rodriguez-Vieitez E, Ni R, Gulyás B, et al. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. Eur J Nucl Med Mol Imaging. 2015;42(7):1119-32.
Rodriguez-Vieitez, E., Ni, R., Gulyás, B., Tóth, M., Häggkvist, J., Halldin, C., Voytenko, L., Marutle, A., & Nordberg, A. (2015). Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. European Journal of Nuclear Medicine and Molecular Imaging, 42(7), 1119-32. https://doi.org/10.1007/s00259-015-3047-0
Rodriguez-Vieitez E, et al. Astrocytosis Precedes Amyloid Plaque Deposition in Alzheimer APPswe Transgenic Mouse Brain: a Correlative Positron Emission Tomography and in Vitro Imaging Study. Eur J Nucl Med Mol Imaging. 2015;42(7):1119-32. PubMed PMID: 25893384.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. AU - Rodriguez-Vieitez,Elena, AU - Ni,Ruiqing, AU - Gulyás,Balázs, AU - Tóth,Miklós, AU - Häggkvist,Jenny, AU - Halldin,Christer, AU - Voytenko,Larysa, AU - Marutle,Amelia, AU - Nordberg,Agneta, Y1 - 2015/04/17/ PY - 2014/11/09/received PY - 2015/03/12/accepted PY - 2015/4/21/entrez PY - 2015/4/22/pubmed PY - 2016/2/10/medline SP - 1119 EP - 32 JF - European journal of nuclear medicine and molecular imaging JO - Eur J Nucl Med Mol Imaging VL - 42 IS - 7 N2 - 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 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. CONCLUSION: The findings provide further in vivo evidence that astrocytosis occurs early in AD, preceding Aβ plaque deposition. SN - 1619-7089 UR - https://www.unboundmedicine.com/medline/citation/25893384/Astrocytosis_precedes_amyloid_plaque_deposition_in_Alzheimer_APPswe_transgenic_mouse_brain:_a_correlative_positron_emission_tomography_and_in_vitro_imaging_study_ DB - PRIME DP - Unbound Medicine ER -