Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons

Söllvander, Sofia; Nikitidou, Elisabeth; Brolin, Robin; Söderberg, Linda; Sehlin, Dag; Lannfelt, Lars; Erlandsson, Anna

doi:10.1186/s13024-016-0098-z

Cited by 180 publications

(215 citation statements)

References 82 publications

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“…We hypothesize that the increase in MAO-B levels may be a consequence of these soluble Aβ species, which may be engulfed by astrocytes [20] and potentially be able to interact with MAO-B at the mitochondria. This hypothesis is also supported by earlier experiments in cell cultures showing that Aβ 25-35 peptide induces expression of MAO-B in cultured rat astrocytes [48].…”

Section: Discussionmentioning

confidence: 99%

“…The left hemisphere was snap frozen on dry ice to be used for biochemical quantification of Aβ and GFAP. The right hemisphere was placed in paraformaldehyde for 24 h. After 24 h, it was cryoprotected in sucrose (10,20, and finally 30 %) and stored in 30 % sucrose at 4°C until cryosectioned for immunohistochemical analysis. The cerebellum, which is largely devoid of Aβ pathology [34], was removed before homogenization of the left hemisphere.…”

Section: Animalsmentioning

confidence: 99%

“…Reactive astrocytes are phagocytic cells that are able to ingest dead cells, neuronal synapses, and protein aggregates of Aβ and α-synuclein [18][19][20][21][22]. Especially in early stages of AD, astrocytes appear to be even more efficient than microglia in engulfing Aβ [22].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

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

et al. 2018

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“…Moore et al [3,46] leave any P3 type peptides unrecorded and not accounted for. Where studies use a capture antibody reactive with the N-terminal of Aβ, further characterisation with antibodies detecting C-terminal aa 40 or 42 can be interpreted as representing Aβ40 or Aβ42 from β-cleavage.…”

Section: Introductionmentioning

confidence: 99%

[P1–193]: Do Anti‐amyloid Beta Protein Antibody Cross Reactivities Confound Alzheimer Disease Research?

Hunter

Brayne

2017

Alzheimer's & Dementia

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Background: Alzheimer disease (AD) research has focussed mainly on the amyloid beta protein (Aβ). However, many Aβ-and P3-type peptides derived from the amyloid precursor protein (APP) and peptides thought to derive from Aβ catabolism share sequence homology. Additionally, conformations can change dependent on aggregation state and solubility leading to significant uncertainty relating to interpretations of immunoreactivity with antibodies raised against Aβ. We review evidence relating to the reactivities of commonly used antibodies including 6F3D, 6E10 and 4G8 and evaluate their reactivity profiles with respect to AD diagnosis and research. Results: Antibody cross-reactivities between Aβ-type, P3-type and Aβ-catabolic peptides confound interpretations of immunoreactivity. More than one antibody is required to adequately characterise Aβ. The relationships between anti-Aβ immunoreactivity, neuropathology and proposed APP cleavages are unclear. Conclusions: We find that the concept of Aβ lacks clarity as a specific entity. Anti-Aβ antibody cross-reactivities lead to significant uncertainty in our understanding of the APP proteolytic system and its role in AD with profound implications for current research and therapeutic strategies.

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“…At the cellular level in the brain, astrocytes and microglia have been reported to have a role in Aβ clearance and degradation . Extracellular chaperones are released by glial cells alone or in association with receptors and/or transporters .…”

Section: Introductionmentioning

confidence: 99%

Evidence that glial cells attenuate G47R transthyretin accumulation in the central nervous system

et al. 2017

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Amyloidogenic protein forms amyloid aggregations at membranes leading to dysfunction of amyloid clearance and amyloidosis. Glial cells function in the clearance and degradation of amyloid β (Aβ) in the brain. This study aimed to clarify the reason why amyloid transthyretin (ATTR) rarely accumulates in the CNS. We pathologically analyzed the relationship between amyloid deposition with basement membranes or glial cells in a rare case of ATTR leptomeningeal amyloidosis. In addition, we compared the cytotoxicity of ATTR G47R, the amyloidosis-causing mutation in the case studied (n = 1), and Aβ in brains from patients with cerebral amyloid angiopathy (n = 6). In the subarachnoid space of the ATTR G47R case, most amyloids accumulated at the components of basement membranes. On the CNS surface, ATTR accumulations were retained by astrocytic end feet. In areas where glial end feet enveloped ATTR, ubiquitination and micro-vacuolation of ATTR was evident. The colocalization of GFAP and ubiquitin was also evident. The accumulation of ATTR G47R in the CNS was negatively correlated with the prevalence of astrocytes. Quantitatively, amyloid deposits along the vessels were mostly partial in cerebral Aβ angiopathy cases and nearly complete along the basement membrane in the ATTR G47R case. The vascular expressions of type IV collagen and smooth muscle actin were severely reduced in areas with ATTR G47R deposition, but not in areas with Aβ deposition. The vascular protein level recovered in the ATTR G47R case when vessels entered into areas of parenchyma that were rich in astrocytes. In addition, the strong interactions between the transthyretin variant and basement membranes may have led to dysfunction of transthyretin clearance and leptomeningeal amyloidosis. The present study was the first to show that glial cells may attenuate G47R transthyretin accumulation in the CNS.

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Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons

Cited by 180 publications

References 82 publications

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

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

[P1–193]: Do Anti‐amyloid Beta Protein Antibody Cross Reactivities Confound Alzheimer Disease Research?

Evidence that glial cells attenuate G47R transthyretin accumulation in the central nervous system

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