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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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CD evidence for BChE-accelerated conversion to β-sheet conformation. CD deconvoluted spectra demonstrate a rapid increase in β-sheet content (upper plot) and rapid decrease in helical content (lower plot) with the addition of rBChE-U, BSP-U, and BSP-K, as compared with the increase in β-sheet content seen with Aβ alone.
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Figure 5: CD evidence for BChE-accelerated conversion to β-sheet conformation. CD deconvoluted spectra demonstrate a rapid increase in β-sheet content (upper plot) and rapid decrease in helical content (lower plot) with the addition of rBChE-U, BSP-U, and BSP-K, as compared with the increase in β-sheet content seen with Aβ alone.

Mentions: The distinct structural features of BSP-K could potentially impair its ability to modulate Aβ conversion to β-sheet conformation. This was assessed by incubating Aβ alone or with BSP peptides and following the CD spectrum for 24 h. Deconvoluted spectra of Aβ samples incubated alone showed a gradual increase in the content of β-sheets, from 26 to 50% within 2.5 h. In contrast, adding rBChE-U or BSP peptides to Aβ accelerated the increase in β-sheet content, which reached an apparent plateau within seconds (50 s, to 48%) (Fig. 5).


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)

CD evidence for BChE-accelerated conversion to β-sheet conformation. CD deconvoluted spectra demonstrate a rapid increase in β-sheet content (upper plot) and rapid decrease in helical content (lower plot) with the addition of rBChE-U, BSP-U, and BSP-K, as compared with the increase in β-sheet content seen with Aβ alone.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: CD evidence for BChE-accelerated conversion to β-sheet conformation. CD deconvoluted spectra demonstrate a rapid increase in β-sheet content (upper plot) and rapid decrease in helical content (lower plot) with the addition of rBChE-U, BSP-U, and BSP-K, as compared with the increase in β-sheet content seen with Aβ alone.
Mentions: The distinct structural features of BSP-K could potentially impair its ability to modulate Aβ conversion to β-sheet conformation. This was assessed by incubating Aβ alone or with BSP peptides and following the CD spectrum for 24 h. Deconvoluted spectra of Aβ samples incubated alone showed a gradual increase in the content of β-sheets, from 26 to 50% within 2.5 h. In contrast, adding rBChE-U or BSP peptides to Aβ accelerated the increase in β-sheet content, which reached an apparent plateau within seconds (50 s, to 48%) (Fig. 5).

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