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The butyrylcholinesterase K variant confers structurally derived risks for Alzheimer pathology.

Podoly E, Shalev DE, Shenhar-Tsarfaty S, Bennett ER, Ben Assayag E, Wilgus H, Livnah O, Soreq H - J. Biol. Chem. (2009)

Bottom Line: Here, we report that BChE-K is inherently unstable as compared with the "usual" BChE (BChE-U), resulting in reduced hydrolytic activity and predicting prolonged acetylcholine maintenance and protection from AD.A synthetic peptide derived from the C terminus of BChE-K (BSP-K), which displayed impaired intermolecular interactions, was less potent in suppressing Abeta oligomerization than its BSP-U counterpart.Dual activity structurally derived changes due to the A539T substitution can thus account for both neuroprotective characteristics caused by sustained acetylcholine levels and elevated AD risk due to inefficient interference with amyloidogenic processes.

View Article: PubMed Central - PubMed

Affiliation: The Alexander Silberman Life Sciences Institute, Hebrew University of Jerusalem, Jerusalem 91904, Israel.

ABSTRACT
The K variant of butyrylcholinesterase (BChE-K, 20% incidence) is a long debated risk factor for Alzheimer disease (AD). The A539T substitution in BChE-K is located at the C terminus, which is essential both for BChE tetramerization and for its capacity to attenuate beta-amyloid (Abeta) fibril formation. Here, we report that BChE-K is inherently unstable as compared with the "usual" BChE (BChE-U), resulting in reduced hydrolytic activity and predicting prolonged acetylcholine maintenance and protection from AD. A synthetic peptide derived from the C terminus of BChE-K (BSP-K), which displayed impaired intermolecular interactions, was less potent in suppressing Abeta oligomerization than its BSP-U counterpart. Correspondingly, highly purified recombinant human rBChE-U monomers suppressed beta-amyloid fibril formation less effectively than dimers, which also protected cultured neuroblastoma cells from Abeta neurotoxicity. Dual activity structurally derived changes due to the A539T substitution can thus account for both neuroprotective characteristics caused by sustained acetylcholine levels and elevated AD risk due to inefficient interference with amyloidogenic processes.

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Related in: MedlinePlus

BChE-induced changes in the Aβ accumulation process. The Aβ aggregation pathway involves a set of mutually dependent reactions in complex equilibria (monomer ⇆ dimer ⇆ oligomer ⇆ fibril). The transition from helical structure to β-sheet conformation was studied by CD, oligomerization was followed by cross-linking, and fibril formation was tracked by ThT fluorescence and TEM. These reactions along the Aβ aggregation pathway are differentially affected by rBChE-U, BSP-U, and BSP-K.
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Figure 8: BChE-induced changes in the Aβ accumulation process. The Aβ aggregation pathway involves a set of mutually dependent reactions in complex equilibria (monomer ⇆ dimer ⇆ oligomer ⇆ fibril). The transition from helical structure to β-sheet conformation was studied by CD, oligomerization was followed by cross-linking, and fibril formation was tracked by ThT fluorescence and TEM. These reactions along the Aβ aggregation pathway are differentially affected by rBChE-U, BSP-U, and BSP-K.

Mentions: Various Aβ aggregation pathways may exist simultaneously, and distinct inhibitors may affect only some of these. For instance, if oligomers are essential intermediates on the pathway to fibril formation, inhibitors that block oligomer formation would ultimately block fibril formation as well. Alternatively, if fibrils and oligomers represent distinct aggregation pathways, some inhibitors might block oligomerization but not fibril formation and vice versa. We followed Aβ oligomerization by cross-linking, and we followed fibril formation by TEM. In both approaches, rBChE-U and BSP peptides attenuated both oligomer and fibril formation, albeit with different efficiencies. This tentatively implies that under the experimental conditions employed, oligomers are fibril intermediates. One possible explanation of the observed attenuation effects is that both rBChE-U and the BSP peptides can induce a shift of Aβ accumulation toward a stabilized Aβ oligomer, as large as 100-mer, if judged by the 1:100 molar ratio of effective inhibition (Fig. 8).


The butyrylcholinesterase K variant confers structurally derived risks for Alzheimer pathology.

Podoly E, Shalev DE, Shenhar-Tsarfaty S, Bennett ER, Ben Assayag E, Wilgus H, Livnah O, Soreq H - J. Biol. Chem. (2009)

BChE-induced changes in the Aβ accumulation process. The Aβ aggregation pathway involves a set of mutually dependent reactions in complex equilibria (monomer ⇆ dimer ⇆ oligomer ⇆ fibril). The transition from helical structure to β-sheet conformation was studied by CD, oligomerization was followed by cross-linking, and fibril formation was tracked by ThT fluorescence and TEM. These reactions along the Aβ aggregation pathway are differentially affected by rBChE-U, BSP-U, and BSP-K.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2719355&req=5

Figure 8: BChE-induced changes in the Aβ accumulation process. The Aβ aggregation pathway involves a set of mutually dependent reactions in complex equilibria (monomer ⇆ dimer ⇆ oligomer ⇆ fibril). The transition from helical structure to β-sheet conformation was studied by CD, oligomerization was followed by cross-linking, and fibril formation was tracked by ThT fluorescence and TEM. These reactions along the Aβ aggregation pathway are differentially affected by rBChE-U, BSP-U, and BSP-K.
Mentions: Various Aβ aggregation pathways may exist simultaneously, and distinct inhibitors may affect only some of these. For instance, if oligomers are essential intermediates on the pathway to fibril formation, inhibitors that block oligomer formation would ultimately block fibril formation as well. Alternatively, if fibrils and oligomers represent distinct aggregation pathways, some inhibitors might block oligomerization but not fibril formation and vice versa. We followed Aβ oligomerization by cross-linking, and we followed fibril formation by TEM. In both approaches, rBChE-U and BSP peptides attenuated both oligomer and fibril formation, albeit with different efficiencies. This tentatively implies that under the experimental conditions employed, oligomers are fibril intermediates. One possible explanation of the observed attenuation effects is that both rBChE-U and the BSP peptides can induce a shift of Aβ accumulation toward a stabilized Aβ oligomer, as large as 100-mer, if judged by the 1:100 molar ratio of effective inhibition (Fig. 8).

Bottom Line: Here, we report that BChE-K is inherently unstable as compared with the "usual" BChE (BChE-U), resulting in reduced hydrolytic activity and predicting prolonged acetylcholine maintenance and protection from AD.A synthetic peptide derived from the C terminus of BChE-K (BSP-K), which displayed impaired intermolecular interactions, was less potent in suppressing Abeta oligomerization than its BSP-U counterpart.Dual activity structurally derived changes due to the A539T substitution can thus account for both neuroprotective characteristics caused by sustained acetylcholine levels and elevated AD risk due to inefficient interference with amyloidogenic processes.

View Article: PubMed Central - PubMed

Affiliation: The Alexander Silberman Life Sciences Institute, Hebrew University of Jerusalem, Jerusalem 91904, Israel.

ABSTRACT
The K variant of butyrylcholinesterase (BChE-K, 20% incidence) is a long debated risk factor for Alzheimer disease (AD). The A539T substitution in BChE-K is located at the C terminus, which is essential both for BChE tetramerization and for its capacity to attenuate beta-amyloid (Abeta) fibril formation. Here, we report that BChE-K is inherently unstable as compared with the "usual" BChE (BChE-U), resulting in reduced hydrolytic activity and predicting prolonged acetylcholine maintenance and protection from AD. A synthetic peptide derived from the C terminus of BChE-K (BSP-K), which displayed impaired intermolecular interactions, was less potent in suppressing Abeta oligomerization than its BSP-U counterpart. Correspondingly, highly purified recombinant human rBChE-U monomers suppressed beta-amyloid fibril formation less effectively than dimers, which also protected cultured neuroblastoma cells from Abeta neurotoxicity. Dual activity structurally derived changes due to the A539T substitution can thus account for both neuroprotective characteristics caused by sustained acetylcholine levels and elevated AD risk due to inefficient interference with amyloidogenic processes.

Show MeSH
Related in: MedlinePlus