The Off-rate of Monomers Dissociating from Amyloid-β Protofibrils

Grüning, Clara S. R.; Klinker, Stefan; Wolff, Martin; Schneider, Mario; Toksöz, Küpra; Nagel-Steger, Luitgard; Willbold, Dieter; Hoyer, Wolfgang

doi:10.1074/jbc.m113.513432

Cited by 28 publications

(27 citation statements)

References 41 publications

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“…The corresponding association rates ( k on,app ) were 0.30±0.02 × 10 −4 s −1 (npAβ) and 0.42±0.05 × 10 −4 s −1 (pS8Aβ). The obtained k off rate of 0.49±0.02 × 10 −4 s −1 for npAβ is comparable to the off-rate value of 1.2 × 10 −4 s −1 previously reported for the protofibrils of wild-type Aβ40 (25 °C, ambient pressure) on the basis of fluorescence measurements 30 . In case of amyloid fibrils formed by an SH3 domain (28 °C, ambient pressure), a dissociation rate of 1.4 × 10 −4 s −1 had been estimated 31 .…”

Section: Resultssupporting

confidence: 88%

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Phosphorylation modifies the molecular stability of β-amyloid deposits

et al. 2016

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Protein aggregation plays a crucial role in neurodegenerative diseases. A key feature of protein aggregates is their ubiquitous modification by phosphorylation. Little is known, however, about the molecular consequences of phosphorylation of protein aggregates. Here we show that phosphorylation of β-amyloid at serine 8 increases the stability of its pathogenic aggregates against high-pressure and SDS-induced dissociation. We further demonstrate that phosphorylation results in an elevated number of hydrogen bonds at the N terminus of β-amyloid, the region that is critically regulated by a variety of post-translational modifications. Because of the increased lifetime of phosphorylated β-amyloid aggregates, phosphorylation can promote the spreading of β-amyloid in Alzheimer pathogenesis. Our study suggests that regulation of the molecular stability of protein aggregates by post-translational modifications is a crucial factor for disease progression in the brain.

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Section: Resultssupporting

confidence: 88%

“…Compared with the extrapolated k off value of ∼0.06 × 10 −4 s −1 at 0 °C in ref. 30 , the use of high pressure in our study has resulted in an about eightfold increase in the monomer dissociation rate of npAβ.…”

Section: Resultsmentioning

confidence: 80%

Phosphorylation modifies the molecular stability of β-amyloid deposits

et al. 2016

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“…Another example compound, ZAβ3W, which is an Affibody protein that prevents Aβ toxicity by sequestration of monomeric Aβ 29 30 , induced reduction of Aβ(1–42) content in fraction 1 and an increase in Aβ(1–42) content in fraction 2, exactly as expected for the formation of a 1:1 ZAβ3W-Aβ complex with an s -value of 2.4 S ( Fig. 5c ).…”

Section: Resultssupporting

confidence: 60%

QIAD assay for quantitating a compound’s efficacy in elimination of toxic Aβ oligomers

Brener

Dunkelmann

Gremer

et al. 2015

Sci Rep

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Strong evidence exists for a central role of amyloid β-protein (Aβ) oligomers in the pathogenesis of Alzheimer’s disease. We have developed a fast, reliable and robust in vitro assay, termed QIAD, to quantify the effect of any compound on the Aβ aggregate size distribution. Applying QIAD, we studied the effect of homotaurine, scyllo-inositol, EGCG, the benzofuran derivative KMS88009, ZAβ3W, the D-enantiomeric peptide D3 and its tandem version D3D3 on Aβ aggregation. The predictive power of the assay for in vivo efficacy is demonstrated by comparing the oligomer elimination efficiency of D3 and D3D3 with their treatment effects in animal models of Alzheimer´s disease.

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“…Grüning et al (2013) detected the appearance of monomers from Ab42 and Ab40 protofibrils: the dissociation rate was 1.4 Â 10 24 and 1.2 Â 10 24 s 21 for Ab42 and Ab40, respectively. Narayan et al (2012) reported Ab40 fibrils releasing soluble Ab40 species at a rate of 9.3 Â 10 25 s…”

Section: Systems Pharmacology Analysis Of the Amyloid Cascade Discussionmentioning

confidence: 99%

Systems Pharmacology Analysis of the Amyloid Cascade after -Secretase Inhibition Enables the Identification of an A 42 Oligomer Pool

Maanen

Steeg

Michener

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The deposition of amyloid-b (Ab) oligomers in brain parenchyma has been implicated in the pathophysiology of Alzheimer's disease. Here we present a systems pharmacology model describing the changes in the amyloid precursor protein (APP) pathway after administration of three different doses (10, 30, and 125 mg/kg) of the b-secretase 1 (BACE1) inhibitor MBi-5 in cisterna magna ported rhesus monkeys. The time course of the MBi-5 concentration in plasma and cerebrospinal fluid (CSF) was analyzed in conjunction with the effect on the concentrations of the APP metabolites Ab42, Ab40, soluble b-amyloid precursor protein (sAPP) a, and sAPPb in CSF. The systems pharmacology model contained expressions to describe the production, elimination, and brain-to-CSF transport for the APP metabolites.Upon administration of MBi-5, a dose-dependent increase of the metabolite sAPPa and dose-dependent decreases of sAPPb and Ab were observed. Maximal inhibition of BACE1 was close to 100% and the IC 50 value was 0.0256 mM (95% confidence interval, 0.0137-0.0375). A differential effect of BACE1 inhibition on Ab40 and Ab42 was observed, with the Ab40 response being larger than the Ab42 response. This enabled the identification of an Ab42 oligomer pool in the systems pharmacology model. These findings indicate that decreases in monomeric Ab responses resulting from BACE1 inhibition are partially compensated by dissociation of Ab oligomers and suggest that BACE1 inhibition may also reduce the putatively neurotoxic oligomer pool.

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The Off-rate of Monomers Dissociating from Amyloid-β Protofibrils

Cited by 28 publications

References 41 publications

Phosphorylation modifies the molecular stability of β-amyloid deposits

Phosphorylation modifies the molecular stability of β-amyloid deposits

QIAD assay for quantitating a compound’s efficacy in elimination of toxic Aβ oligomers

Systems Pharmacology Analysis of the Amyloid Cascade after -Secretase Inhibition Enables the Identification of an A 42 Oligomer Pool

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