Malin Olsen1, Ximena Aguilar1, Dag Sehlin1, Xiaotian T Fang1, Gunnar Antoni2,3, Anna Erlandsson1, Stina Syvänen4. 1. Department of Public Health and Caring Sciences/Geriatrics, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, SE-751 85, Uppsala, Sweden. 2. Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Dag Hammarskjölds väg 20, SE-751 83, Uppsala, Sweden. 3. PET Centre, Uppsala University Hospital, Entrance 70, Sjukhusvägen 10, SE-75185, Uppsala, Sweden. 4. Department of Public Health and Caring Sciences/Geriatrics, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, SE-751 85, Uppsala, Sweden. stina.syvanen@pubcare.uu.se.
Abstract
PURPOSE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-L-[11C]deprenyl ([11C]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during Aβ pathology progression. PROCEDURES: APPArcSwe mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [11C]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. Aβ and GFAP levels were also measured with ELISA in brain homogenates. RESULTS: The intrabrain levels of aggregated Aβ and reactive astrocytes were found to be elevated in APPArcSwe compared with WT mice. GFAP and vimentin expression increased with age, i.e., with Aβ pathology, in the APPArcSwe mice. This was not the case for in vivo marker [11C]DED that showed elevated binding of the same magnitude in APPArcSwe mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP. CONCLUSIONS: MAO-B levels are increased early in Aβ pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant Aβ plaque formation. Thus, [11C]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of AD progression but does not measure the total extent of astrogliosis at advanced stages of Aβ pathology.
PURPOSE:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-L-[11C]deprenyl ([11C]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during Aβ pathology progression. PROCEDURES: APPArcSwe mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [11C]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. Aβ and GFAP levels were also measured with ELISA in brain homogenates. RESULTS: The intrabrain levels of aggregated Aβ and reactive astrocytes were found to be elevated in APPArcSwe compared with WT mice. GFAP and vimentin expression increased with age, i.e., with Aβ pathology, in the APPArcSwe mice. This was not the case for in vivo marker [11C]DED that showed elevated binding of the same magnitude in APPArcSwe mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP. CONCLUSIONS:MAO-B levels are increased early in Aβ pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant Aβ plaque formation. Thus, [11C]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of AD progression but does not measure the total extent of astrogliosis at advanced stages of Aβ pathology.
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