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

Abstract

Purpose: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloidbeta (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-[ 11 C]deprenyl ([ 11 C]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: APP ArcSwe mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [ 11 C]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 APP ArcSwe compared with WT mice. GFAP and vimentin expression increased with age, i.e., with Aβ pathology, in the APP ArcSwe mice. This was not the case for in vivo marker [ 11 C]DED that showed elevated binding of the same magnitude in APP ArcSwe 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, [ 11 C]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-017-1153-z) contains supplementary material, which is available to authorized users.Correspondence to: Stina Syvänen; e-mail: stina.syvanen@pubcare.uu.se AD progression but does not measure the total extent of astrogliosis at advanced stages of Aβ pathology.

Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure

“…However, importantly, clustering of GFAP was observed both in the EC and HPC of 10-month-old APP/PS1 mice, and coverage of this clustered GFAP in the HPC was increased as expected. Considering that clustered GFAP was more prominent in APP/PS1 mice, and we observed a similar pattern of Aβ plaque load in parallel series of the same brain stained for Aβ, clustering of GFAP is probably due to accumulation of GFAP around Aβ plaques [76]. The reduction in global versus the increase in clustered GFAP coverage is in line with a previous study where general astroglial cytoskeletal atrophy was observed, while GFAP+ astrocytes surrounding Aβ plaques were hypertrophic in the HPC of 18-month-old 3xTG AD mice [77].…”

Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure

“…However, importantly, clustering of GFAP was observed both in the EC and HPC of 10-month-old APP/PS1 mice, and coverage of this clustered GFAP in the HPC was increased as expected. Considering that clustered GFAP was more prominent in APP/PS1 mice, and we observed a similar pattern of Aβ plaque load in parallel series of the same brain stained for Aβ, clustering of GFAP is probably due to accumulation of GFAP around Aβ plaques [75]. The reduction in global versus the increase in clustered GFAP coverage is in line with a previous study where general astroglial cytoskeletal atrophy was observed, while GFAP + astrocytes surrounding Aβ plaques were hypertrophic in the HPC of 18-month-old 3xTG AD mice [76].…”

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

“…The pathogenesis is characterized by amyloid‐β deposition, hyperphosphorylation of tau, and neuroinflammation along with dramatic astrogliosis (Hascup et al, ). The astrogliosis occurs following the overexpression of enzyme monoamine oxidase‐B during amyloid‐β plaque evoked reactive inflammation (Olsen et al, ). Astrocytic response by astrogliosis, injury and atrophy can be either neuroprotective or deleterious.…”