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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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rBChE-U attenuates fibril formation more than BSP peptides and induces fibril disassembly. A, computer-processed TEM photomicrographs following 24-h incubations of Aβ alone or with BSP-U, BSP-K, or rBChE-U. B, fibrils were clustered into groups according to their length. Note that both BSP peptides shifted the Aβ fibrils from relatively long to numerous short fibrils, whereas rBChE-U suppressed the formation of fibrils of all length groups. C and D, Aβ alone or with rBChE-U added after different incubation times (shown by arrows). Plots present the fibril number or branches versus fibril length. Note the apparent disassembly of preformed fibrils. E, ThT fluorescence curves for the BSP-U and the BSP-K peptides. Note that BSP-U, but not BSP-K, was capable of repressing the ThT increment induced by Aβ. FU, fluorescence units.
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Figure 7: rBChE-U attenuates fibril formation more than BSP peptides and induces fibril disassembly. A, computer-processed TEM photomicrographs following 24-h incubations of Aβ alone or with BSP-U, BSP-K, or rBChE-U. B, fibrils were clustered into groups according to their length. Note that both BSP peptides shifted the Aβ fibrils from relatively long to numerous short fibrils, whereas rBChE-U suppressed the formation of fibrils of all length groups. C and D, Aβ alone or with rBChE-U added after different incubation times (shown by arrows). Plots present the fibril number or branches versus fibril length. Note the apparent disassembly of preformed fibrils. E, ThT fluorescence curves for the BSP-U and the BSP-K peptides. Note that BSP-U, but not BSP-K, was capable of repressing the ThT increment induced by Aβ. FU, fluorescence units.

Mentions: Transmission electron microscopy (TEM) was used to quantify longer and more developed Aβ fibrils, formed in the presence or absence of rBChE-U and BSP peptides. Following 48 h of incubation, Aβ alone formed mostly 50–60-nm-long fibrils, with some fibrils reaching up to 300 nm. In the presence of either of the BSP peptides, however, the majority of Aβ fibrils were 20–30-nm long with none longer than 120 nm. In the presence of rBChE-U, a dramatic reduction in the formation of fibrils of all length groups was seen, as compared with Aβ incubated alone or with BSP peptides (Fig. 7A).


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)

rBChE-U attenuates fibril formation more than BSP peptides and induces fibril disassembly. A, computer-processed TEM photomicrographs following 24-h incubations of Aβ alone or with BSP-U, BSP-K, or rBChE-U. B, fibrils were clustered into groups according to their length. Note that both BSP peptides shifted the Aβ fibrils from relatively long to numerous short fibrils, whereas rBChE-U suppressed the formation of fibrils of all length groups. C and D, Aβ alone or with rBChE-U added after different incubation times (shown by arrows). Plots present the fibril number or branches versus fibril length. Note the apparent disassembly of preformed fibrils. E, ThT fluorescence curves for the BSP-U and the BSP-K peptides. Note that BSP-U, but not BSP-K, was capable of repressing the ThT increment induced by Aβ. FU, fluorescence units.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: rBChE-U attenuates fibril formation more than BSP peptides and induces fibril disassembly. A, computer-processed TEM photomicrographs following 24-h incubations of Aβ alone or with BSP-U, BSP-K, or rBChE-U. B, fibrils were clustered into groups according to their length. Note that both BSP peptides shifted the Aβ fibrils from relatively long to numerous short fibrils, whereas rBChE-U suppressed the formation of fibrils of all length groups. C and D, Aβ alone or with rBChE-U added after different incubation times (shown by arrows). Plots present the fibril number or branches versus fibril length. Note the apparent disassembly of preformed fibrils. E, ThT fluorescence curves for the BSP-U and the BSP-K peptides. Note that BSP-U, but not BSP-K, was capable of repressing the ThT increment induced by Aβ. FU, fluorescence units.
Mentions: Transmission electron microscopy (TEM) was used to quantify longer and more developed Aβ fibrils, formed in the presence or absence of rBChE-U and BSP peptides. Following 48 h of incubation, Aβ alone formed mostly 50–60-nm-long fibrils, with some fibrils reaching up to 300 nm. In the presence of either of the BSP peptides, however, the majority of Aβ fibrils were 20–30-nm long with none longer than 120 nm. In the presence of rBChE-U, a dramatic reduction in the formation of fibrils of all length groups was seen, as compared with Aβ incubated alone or with BSP peptides (Fig. 7A).

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