Clusterin (Apo J) Protects Against In Vitro Amyloid‐β(1–40) Neurotoxicity

Boggs, Leonard N.; Fuson, Kimberly S.; Baez, Melvyn; Churgay, Lisa M.; McClure, Don B.; Becker, Gerald W.; May, Patrick C.

doi:10.1046/j.1471-4159.1996.67031324.x

Cited by 95 publications

(55 citation statements)

References 24 publications

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“…[111][112][113][114] ApoJ has been shown to interact with Ab 115-117 and alter its ability to form fibrils [117][118][119] and modifies Abmediated neurotoxicity. 32,119,120 It has also been shown in vivo that expression of apoJ either on its own or together with apoE reduces plaque formation, soluble and insoluble brain Ab40/42 levels and CSF Ab40/42 levels in PDAPP transgenic mice. 121 This effect was shown not to be because of altered Ab production, as APP processing was not altered in the presence or absence of apoE and/or apoJ.…”

Section: Apolipoprotein J-mediated Transport Of Ab Across Bbbmentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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Section: Apolipoprotein J-mediated Transport Of Ab Across Bbbmentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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“…In all our experiments, the oligomers are formed before adding the chaperones, showing that the protective action of the latter also includes neutralization of toxic oligomers after they have formed. This protective mechanism is not entirely undescribed, but evidence has been very sparse in the past, with reports often being contradictory and with undefined mechanisms (9,(18)(19)(20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers

Mannini

Cascella

Zampagni

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

143

156

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Chaperones are the primary regulators of the proteostasis network and are known to facilitate protein folding, inhibit protein aggregation, and promote disaggregation and clearance of misfolded aggregates inside cells. We have tested the effects of five chaperones on the toxicity of misfolded oligomers preformed from three different proteins added extracellularly to cultured cells. All the chaperones were found to decrease oligomer toxicity significantly, even at very low chaperone/protein molar ratios, provided that they were added extracellularly rather than being overexpressed in the cytosol. Infrared spectroscopy and site-directed labeling experiments using pyrene ruled out structural reorganizations within the discrete oligomers. Rather, confocal microscopy, SDS-PAGE, and intrinsic fluorescence measurements indicated tight binding between oligomers and chaperones. Moreover, atomic force microscopy imaging indicated that larger assemblies of oligomers are formed in the presence of the chaperones. This suggests that the chaperones bind to the oligomers and promote their assembly into larger species, with consequent shielding of the reactive surfaces and a decrease in their diffusional mobility. Overall, the data indicate a generic ability of chaperones to neutralize extracellular misfolded oligomers efficiently and reveal that further assembly of protein oligomers into larger species can be an effective strategy to neutralize such extracellular species.protein homeostasis | protein misfolding | protein aggregates | amyloid | extracellular chaperones

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“…When tested against neuronal cell lines, under certain specific conditions, clusterin and α 2 M were shown to promote the neurotoxicity of Aβ (clusterin -PC12 cells (Oda et al, 1995); α 2 M -LAN5 cells (Fabrizi et al, 2001)). In stark contrast, using primary rat mixed neuronal cultures, others have demonstrated that clusterin and α 2 M can protect cells from Aβ toxicity (Boggs et al, 1996;Du et al, 1997). Even within individual studies, depending on the conditions used, clusterin was shown both to protect cells and to promote cytotoxicity.…”

Section: The In Vitro Effects Of Ecs On Amyloid Toxicitymentioning

confidence: 95%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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Clusterin (Apo J) Protects Against In Vitro Amyloid‐β(1–40) Neurotoxicity

Cited by 95 publications

References 24 publications

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers

Extracellular Chaperones and Amyloids

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