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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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BSP-K sustains less cross-linked Aβ oligomers in solution than BSP-U. A, 16% Tris-Tricine gel demonstrating BSP peptide interference with oligomerization of Aβ. MW, molecular weight markers; no CL, no cross-linking. B, the cross-linking reaction. Prot, protein. C, quantification of Aβ dimers and trimers in solution, in the presence of BSP-K and BSP-U.
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Figure 6: BSP-K sustains less cross-linked Aβ oligomers in solution than BSP-U. A, 16% Tris-Tricine gel demonstrating BSP peptide interference with oligomerization of Aβ. MW, molecular weight markers; no CL, no cross-linking. B, the cross-linking reaction. Prot, protein. C, quantification of Aβ dimers and trimers in solution, in the presence of BSP-K and BSP-U.

Mentions: Further studies of Aβ oligomerization involved cross-linking of Aβ in the presence or absence of BSP-U or BSP-K and separation of the soluble fractions by SDS-PAGE (Fig. 6). Aβ alone precipitated rapidly, within 4 h. Both BSP peptides prolonged the time Aβ oligomers remained in solution, but BSP-U prolonged the persistence of amyloid oligomers in solution more effectively than BSP-K; after 8 h of incubation, no oligomeric forms of Aβ remained in the soluble phase in the presence of BSP-K, whereas in the presence of BSP-U, they lasted nearly 22 h. This supports the view that BSP-K is less capable of interacting both with PolyP and with Aβ than BSP-U.


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)

BSP-K sustains less cross-linked Aβ oligomers in solution than BSP-U. A, 16% Tris-Tricine gel demonstrating BSP peptide interference with oligomerization of Aβ. MW, molecular weight markers; no CL, no cross-linking. B, the cross-linking reaction. Prot, protein. C, quantification of Aβ dimers and trimers in solution, in the presence of BSP-K and BSP-U.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: BSP-K sustains less cross-linked Aβ oligomers in solution than BSP-U. A, 16% Tris-Tricine gel demonstrating BSP peptide interference with oligomerization of Aβ. MW, molecular weight markers; no CL, no cross-linking. B, the cross-linking reaction. Prot, protein. C, quantification of Aβ dimers and trimers in solution, in the presence of BSP-K and BSP-U.
Mentions: Further studies of Aβ oligomerization involved cross-linking of Aβ in the presence or absence of BSP-U or BSP-K and separation of the soluble fractions by SDS-PAGE (Fig. 6). Aβ alone precipitated rapidly, within 4 h. Both BSP peptides prolonged the time Aβ oligomers remained in solution, but BSP-U prolonged the persistence of amyloid oligomers in solution more effectively than BSP-K; after 8 h of incubation, no oligomeric forms of Aβ remained in the soluble phase in the presence of BSP-K, whereas in the presence of BSP-U, they lasted nearly 22 h. This supports the view that BSP-K is less capable of interacting both with PolyP and with Aβ than BSP-U.

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