Extracellular chaperones modulate the effects of Alzheimer’s patient cerebrospinal fluid on Aβ1-42 toxicity and uptake

Yerbury, Justin J.; Wilson, Mark R.

doi:10.1007/s12192-009-0122-0

Cited by 53 publications

(41 citation statements)

References 45 publications

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“…Along similar lines, in the presence of α 2 M, Aβ was cytotoxic to LRP-negative LAN5 cells but not when the LAN5 cells were transfected with LRP (175). When Aβ is added into AD patient CSF, it is more toxic to SH-SY5Y cells than Aβ added into control CSF; adding ECs (clusterin, α 2 M and haptoglobin) suppresses this toxicity and this effect coincides with a more efficient cellular uptake of Aβ (112). Furthermore, it has been demonstrated that clusterin-Aβ complexes bind to the receptor megalin on the surface of mouse teratocarcinoma F9 cells, and are subsequently internalized, via receptor mediated endocytosis, transported to lysosomes and degraded (195).…”

Section: Ec-mediated Clearance Of Protein Aggregatesmentioning

confidence: 74%

“…Investigation of the chaperone activity of α 2 M against stress-induced amorphous protein aggregation is currently limited to a single study which suggested that this activity was abolished by protease activation, however, α 2 M retained the ability to trap proteases after binding to misfolded proteins and α 2 M-protease-misfolded protein complexes were recognized by LRP (111). α 2 M has been shown to inhibit amyloid formation by a large number of substrates (86) and to protect cells against Aβ toxicity in vitro (112,113). As for the other ECs, α 2 M appears to suppress amyloid formation by interacting with prefibrillar species that occur early in the aggregation process (86).…”

Section: α 2 -Macroglobulin (α 2 M)mentioning

confidence: 97%

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Extracellular Chaperones and Proteostasis

Wyatt

Yerbury

Ecroyd

et al. 2013

Annu. Rev. Biochem.

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157

173

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There is a family of currently untreatable serious human diseases that arise from the inappropriate misfolding and aggregation of extracellular proteins. At present our understanding of mechanisms that operate to maintain proteostasis in extracellular body fluids is limited but has significantly advanced with the discovery of a small but growing family of constitutively secreted extracellular chaperones (ECs). The available evidence strongly suggests that these chaperones act as both sensors and disposal-mediators of misfolded proteins in extracellular fluids, thereby normally protecting us from disease pathologies. It is critically important to further increase our understanding of the mechanisms that operate to effect extracellular proteostasis, as this will be essential knowledge upon which to base the development of effective therapies for some of the world's most debilitating, costly and intractable diseases.

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Section: Ec-mediated Clearance Of Protein Aggregatesmentioning

confidence: 74%

Section: α 2 -Macroglobulin (α 2 M)mentioning

confidence: 97%

Extracellular Chaperones and Proteostasis

Wyatt

Yerbury

Ecroyd

et al. 2013

Annu. Rev. Biochem.

Self Cite

157

173

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“…In addition, it would be interesting to know where GRP78 is located within the neurons in AD tissues, as its functions depend on localization as discussed above. Importantly, the extracellular chaperone α 2 -M, a ligand of GRP78 at the plasma membrane, is co-localized with plaques in AD (Yerbury and Wilson, 2010), and it has been shown both to protect cells from Aβ toxicity and to favor Aβ removal from the brain (reviewed in Yerbury and Wilson, 2010). It is likely that some of these beneficial effects occur through the intervention of GRP78, although this has not been demonstrated yet.…”

Section: Grp78 In Neurodegenerative Processesmentioning

confidence: 99%

GRP78 at the Centre of the Stage in Cancer and Neuroprotection

2017

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The 78-kDa glucose-regulated protein GRP78, also known as BiP and HSP5a, is a multifunctional protein with activities far beyond its well-known role in the unfolded protein response (UPR) which is activated after endoplasmic reticulum (ER) stress in the cells. Most of these newly discovered activities depend on its position within the cell. GRP78 is located mainly in the ER, but it has also been observed in the cytoplasm, the mitochondria, the nucleus, the plasma membrane, and secreted, although it is dedicated mostly to engage endogenous cytoprotective processes. Hence, GRP78 may control either UPR and macroautophagy or may activated phosphatidylinositol 3-kinase (PI3K)/AKT pro-survival pathways. GRP78 influences how tumor cells survive, proliferate, and develop chemoresistance. In neurodegeneration, endogenous mechanisms of neuroprotection are frequently insufficient or dysregulated. Lessons from tumor biology may give us clues about how boosting endogenous neuroprotective mechanisms in age-related neurodegeneration. Herein, the functions of GRP78 are revealed at the center of the stage of apparently opposite sites of the same coin regarding cytoprotection: neurodegeneration and cancer. The goal is to give a comprehensive and critical review that may serve to guide future experiments to identify interventions that will enhance neuroprotection.

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“…These findings suggest that ␣2M plays an important role in controlling the amyloid fibril formation of ␤2-m by binding to denatured monomeric/oligomeric ␤2-m. In addition, it has been reported that ␣2M protects cells from the toxicity of amyloid ␤ peptide and promotes the uptake of amyloid ␤ peptide in macrophagelike cells (34), suggesting that ␣2M and other extracellular chaperones are important elements of a system of extracellular protein folding quality control that protects against the toxicity and accumulation of amyloid ␤ peptide. When the efficient protein quality control machinery of ␣2M and other extracellular chaperones is overwhelmed, the denatured ␤2-m and other amyloidogenic proteins may form extracellular amyloid deposits in vivo (12,16).…”

Section: Figure 5 Interaction Of Tetrameric and Dimeric ␣2m With ␤2-mentioning

confidence: 99%

Inhibition of β2-Microglobulin Amyloid Fibril Formation by α2-Macroglobulin

Ozawa

Hara

Lee

et al. 2011

Journal of Biological Chemistry

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The relationship between various amyloidoses and chaperones is gathering attention. In patients with dialysis-related amyloidosis, ␣ 2 -macroglobulin (␣2M), an extracellular chaperone, forms a complex with ␤ 2 -microglobulin (␤2-m), a major component of amyloid fibrils, but the molecular mechanisms and biological implications of the complex formation remain unclear. Here, we found that ␣2M substoichiometrically inhibited the ␤2-m fibril formation at a neutral pH in the presence of SDS, a model for anionic lipids. Binding analysis showed that the binding affinity between ␣2M and ␤2-m in the presence of SDS was higher than that in the absence of SDS. Importantly, SDS dissociated tetrameric ␣2M into dimers with increased surface hydrophobicity. Western blot analysis revealed that both tetrameric and dimeric ␣2M interacted with SDS-denatured ␤2-m. At a physiologically relevant acidic pH and in the presence of heparin, ␣2M was also dissociated into dimers, and both tetrameric and dimeric ␣2M interacted with ␤2-m, resulting in the inhibition of fibril growth reaction. These results suggest that under conditions where native ␤2-m is denatured, tetrameric ␣2M is also converted to dimeric form with exposed hydrophobic surfaces to favor the hydrophobic interaction with denatured ␤2-m, thus dimeric ␣2M as well as tetrameric ␣2M may play an important role in controlling ␤2-m amyloid fibril formation.A number of proteins and peptides can misfold into ␤-sheetrich structures, called amyloid fibrils (1). The deposition of amyloid fibrils in intra-and extracellular spaces is responsible for more than 40 serious diseases, including Alzheimer and Parkinson diseases and dialysis-related amyloidosis (DRA) 2 (1). ␤ 2 -Microglobulin (␤2-m) is a major structural component of amyloid fibrils in DRA, a common and serious complication in long term hemodialysis patients (2). The formation of ␤2-m amyloid fibrils is thought to be induced by partial unfolding of ␤2-m (3, 4). Several groups have established conditions under which ␤2-m amyloid fibril formation occurs at a neutral pH (5-11). We found that ␤2-m amyloid fibrils are formed at a neutral pH in the presence of SDS (11). SDS below its critical micelle concentration unfolds the compact structure of ␤2-m to an amyloidogenic conformer and stabilizes the extended amyloid fibrils. SDS is an anionic detergent that mimics some characteristics of biological membranes and is considered to be a good model for anionic lipids. We recently reported that some lysophospholipids, especially lysophosphatidic acid as well as nonesterified fatty acids induce the extension of ␤2-m amyloid fibrils at a neutral pH by partially unfolding the compact structure of ␤2-m to an amyloidogenic conformer as well as by stabilizing the extended fibrils (6, 8). Although many groups have proposed the mechanisms by which ␤2-m amyloid fibrils are formed under physiological conditions, the biological machineries to inhibit the formation and deposition of ␤2-m amyloid fibrils are poorly understood (12).␣ 2 -Macroglobulin (...

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Extracellular chaperones modulate the effects of Alzheimer’s patient cerebrospinal fluid on Aβ1-42 toxicity and uptake

Cited by 53 publications

References 45 publications

Extracellular Chaperones and Proteostasis

Extracellular Chaperones and Proteostasis

GRP78 at the Centre of the Stage in Cancer and Neuroprotection

Inhibition of β2-Microglobulin Amyloid Fibril Formation by α2-Macroglobulin

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