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

Molecular imaging and biology (2018-01-04)
Malin Olsen, Ximena Aguilar, Dag Sehlin, Xiaotian T Fang, Gunnar Antoni, Anna Erlandsson, Stina Syvänen
ABSTRACT

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. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Vimentin Antibody, serum, Chemicon®
Sigma-Aldrich
Monoclonal Anti-Glial Fibrillary Acidic Protein (GFAP) antibody produced in mouse, clone G-A-5, ascites fluid
Sigma-Aldrich
Anti-MAOB antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution