A Kinetic Analysis of the Mechanism of β-Amyloid Induced G Protein Activation

Wang, Steven S.‐S.; Kazantzi, Vasiliki; Good, Theresa A.

doi:10.1006/jtbi.2003.3189

Cited by 9 publications

(8 citation statements)

References 46 publications

(38 reference statements)

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“…To this end, efforts have been made in the past to use other cellular responses as indicators of eventual A␤ toxic effect. These indicator responses include A␤-induced G-protein activation (Rymer and Good, 2001;Wang et al, 2003), acetylcholinesterase expression (Zhang et al, 2003), oxidative stress responses (Shearman et al, 1994;Varadarajan et al, 2000;White et al, 1998), changes in ion channel function (Good and Murphy, 1996;Weiss et al, 1994) and changes in cell membrane potential (Blanchard et al, 2002;Bobich et al, 2004). While these methods are more rapid than the traditional toxicity assays, it is hard to correlate those cellular responses directly to an eventual toxic response.…”

Section: Introductionmentioning

confidence: 97%

A rapid method to measure beta-amyloid induced neurotoxicity in vitro

Patel

Good

2007

Journal of Neuroscience Methods

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Section: Introductionmentioning

confidence: 97%

A rapid method to measure beta-amyloid induced neurotoxicity in vitro

Patel

Good

2007

Journal of Neuroscience Methods

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“…Reverse structure Abeta , shorter fragments of the peptide (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and two unrelated peptides (bradykinin and bombesin) did not cause hydrolysis of fluorescein dibutyrate (supplementary Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

“…The hydrolytic properties of Abeta were confirmed by Matsunaga and co-workers [10,11]. Moreover, an increase in Abeta-induced GTP hydrolysis rate has been reported [12]. Although at this stage it is difficult to define the exact biological significance of Abeta-mediated hydrolysis, the ubiquity of ester bonds prompted us to further characterize the observed biochemical properties of Abeta.…”

mentioning

confidence: 75%

Discrete conformational changes as regulators of the hydrolytic properties of beta‐amyloid (1–40)

et al. 2006

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Beta‐amyloid (1–40) (Abeta), the main component of senile plaques seen in the brains of Alzheimer's disease patients, was found to be toxic both as fibrils and smaller soluble globular aggregates. The hydrolytic properties of Abeta, a new biochemical activity described previously [Brzyska M, Bacia A & Elbaum D (2001) Eur J Biochem268, 3443–3454], may contribute to its overall toxicity. In this study, the hydrolysis of fluorescein ester series was studied under predetermined conditions affecting Abeta hydrophobicity and conformation. Reaction products of the most effectively decomposed ester (dibutyrate) were characterized using HPLC and ESI‐MS. Hydrophobicity of Abeta, as measured by bis‐8‐anilinonaphthalene fluorescence, correlated with its hydrolytic abilities. FTIR and CD data analysis showed a relationship between enhanced hydrolytic abilities and Abeta structure. Seriously limited hydrolysis caused by higher peptide concentrations is consistent with monomeric/dimeric Abeta species participation in the process, confirmed by thioflavine T binding. Inhibition of hydrolysis was caused by β‐sheet breaker peptide (LPFFD), indicating that the Abeta central hydrophobic cluster (amino acids 17–21) participates in the process. The reported Abeta properties suggest that small conformational alterations of the peptide structure may have a pronounced effect on its functions and biological activity.

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“…Although there may be differences in tertiary structure,48 backbone solvent accessibility,35, 29 or stability between the toxic intermediate and the fibril,46 it appears that there are at least some molecular level structural similarities between the toxic intermediate and the mature fibril. Second, Aβ fibrils are still toxic46 and have been shown to have a wide range of biological activities 46, 50. Thus, in the absence of a high resolution structure of an Aβ aggregation intermediate structure, we believe that the fibril structure could serve as a reasonable approximation for other β‐sheet fibril‐like aggregates.…”

Section: Discussionmentioning

confidence: 99%

Structurally distinct toxicity inhibitors bind at common loci on β‐amyloid fibril

2010

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The accumulation of aggregated b-Amyloid (Ab) in the brain is a hallmark of Alzheimer's disease and is thought to play a role in the neurotoxicity associated with the disease. The mechanism by which Ab aggregates induce toxicity is uncertain. Nonetheless, several small molecules have been found to interact with Ab fibrils and to prevent their toxicity. In this paper we studied the binding of these known toxicity inhibitors to Ab fibrils, as a means to explore surfaces or loci on Ab aggregates that may be significant in the mechanism of action of these inhibitors. We believe knowledge of these binding loci will provide insight into surfaces on the Ab fibrils important in Ab biological activity. The program DOCK was used to computationally dock the inhibitors to an Ab fibril. The inhibitors docked at two shared binding loci, near Lys28 and at the C-termini near Asn27 and Val39. The docking predictions were experimentally verified using lysine specific chemical modifications and Ab fibrils mutated at Asn27. We found that both Congo red and Myricetin, despite being structurally different, bound at the same two sites. Additionally, our data suggests that three additional Ab toxicity inhibitors may also bind in one of the sites. Identification of these common binding loci provides targets on the Ab fibril surface that can be tested in the future for their role in Ab biological activity.

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A Kinetic Analysis of the Mechanism of β-Amyloid Induced G Protein Activation

Cited by 9 publications

References 46 publications

A rapid method to measure beta-amyloid induced neurotoxicity in vitro

A rapid method to measure beta-amyloid induced neurotoxicity in vitro

Discrete conformational changes as regulators of the hydrolytic properties of beta‐amyloid (1–40)

Structurally distinct toxicity inhibitors bind at common loci on β‐amyloid fibril

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