Large Aggregates Are the Major Soluble Aβ Species in AD Brain Fractionated with Density Gradient Ultracentrifugation

Sehlin, Dag; Englund, Hillevi; Simu, Barbro; Karlsson, Mikael; Ingelsson, Martin; Nikolajeff, Fredrik; Lannfelt, Lars; Pettersson, Frida Ekholm

doi:10.1371/journal.pone.0032014

Cited by 90 publications

(74 citation statements)

References 53 publications

(73 reference statements)

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“…Using density gradient centrifugation to separate protein aggregates from cell organelles such as mitochondria (Sehlin et al , 2012), we observed that a fraction of the Aβ42 peptide added to the experiment directly associated with mitochondria. Of interest, the presence of precursor proteins changed the behavior of Aβ42, as the amount of mitochondria-associated material decreased, whereas the aggregated forms increased.…”

Section: Discussionmentioning

confidence: 99%

Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process

Cenini

Rüb

Bruderek

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process

Cenini

Rüb

Bruderek

et al. 2016

MBoC

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“…The preparation was incubated for 30 minutes at 37°C and then centrifuged at 16 000 × g for 5 minutes to pellet potential large aggregates. The supernatants were further purified from monomers by size exclusion chromatography (Superdex 75 column, GE Healthcare, Sweden) in 0.05 M Phosphate buffer, 0.15 M NaCl, pH 7.4, and protofibrils were collected in the void fraction as previously described . The generated Aβ protofibrils were used for the standard curves in the oligomer/protofibril assays.…”

Section: Methodsmentioning

confidence: 99%

Rapid amyloid‐β oligomer and protofibril accumulation in traumatic brain injury

et al. 2017

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Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.

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“…The ELISA was performed as previously described [34]. In addition to Aβ40, soluble Aβ protofibril levels in brain TBS homogenates was measured as previously described [34,39]. Aβ concentrations were determined from a standard curve of serially diluted synthetic Aβ40 and Aβ protofibrils respectively.…”

Section: Biochemical Analysis Of Gfap and Aβ Pathologymentioning

confidence: 99%

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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Large Aggregates Are the Major Soluble Aβ Species in AD Brain Fractionated with Density Gradient Ultracentrifugation

Cited by 90 publications

References 53 publications

Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process

Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process

Rapid amyloid‐β oligomer and protofibril accumulation in traumatic brain injury

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

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