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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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The BChE gene and its usual U and K variant protein products. A, BChE location on chromosome 3q26.1-q26.2 and its gene structure (56). B, the C-terminal DNA and amino acid sequences of BChE-U and -K. The predicted secondary structure of the amino acid substitution (enlarged) is shown above the sequences. C, histograms of measured BChE activity in apparently healthy carriers of the UU, UK, and KK genotypes. Units are nmol of acetylthiocholine hydrolyzed/min/ml serum.
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Figure 1: The BChE gene and its usual U and K variant protein products. A, BChE location on chromosome 3q26.1-q26.2 and its gene structure (56). B, the C-terminal DNA and amino acid sequences of BChE-U and -K. The predicted secondary structure of the amino acid substitution (enlarged) is shown above the sequences. C, histograms of measured BChE activity in apparently healthy carriers of the UU, UK, and KK genotypes. Units are nmol of acetylthiocholine hydrolyzed/min/ml serum.

Mentions: The BChE genotype (Fig. 1, A and B) was determined using nucleated blood cell DNA from apparently healthy volunteers who also donated serum for hydrolytic activity measurements. The observed genotype distribution included 72.0% UU, 23.2% UK, and 4.4% KK variants, consistent with the Hardy-Weinberg equilibrium. The corresponding mean calculated ATCh hydrolytic activities of serum BChE from these subjects were 1103.31 ± 219.34, 1031.16 ± 198.56, and 949.05 ± 203.47 (p = 0.011) (Fig. 1C). The decline in ATCh hydrolytic activity from heterozygous to homozygous carriers indicated gene dose dependence.


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)

The BChE gene and its usual U and K variant protein products. A, BChE location on chromosome 3q26.1-q26.2 and its gene structure (56). B, the C-terminal DNA and amino acid sequences of BChE-U and -K. The predicted secondary structure of the amino acid substitution (enlarged) is shown above the sequences. C, histograms of measured BChE activity in apparently healthy carriers of the UU, UK, and KK genotypes. Units are nmol of acetylthiocholine hydrolyzed/min/ml serum.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: The BChE gene and its usual U and K variant protein products. A, BChE location on chromosome 3q26.1-q26.2 and its gene structure (56). B, the C-terminal DNA and amino acid sequences of BChE-U and -K. The predicted secondary structure of the amino acid substitution (enlarged) is shown above the sequences. C, histograms of measured BChE activity in apparently healthy carriers of the UU, UK, and KK genotypes. Units are nmol of acetylthiocholine hydrolyzed/min/ml serum.
Mentions: The BChE genotype (Fig. 1, A and B) was determined using nucleated blood cell DNA from apparently healthy volunteers who also donated serum for hydrolytic activity measurements. The observed genotype distribution included 72.0% UU, 23.2% UK, and 4.4% KK variants, consistent with the Hardy-Weinberg equilibrium. The corresponding mean calculated ATCh hydrolytic activities of serum BChE from these subjects were 1103.31 ± 219.34, 1031.16 ± 198.56, and 949.05 ± 203.47 (p = 0.011) (Fig. 1C). The decline in ATCh hydrolytic activity from heterozygous to homozygous carriers indicated gene dose dependence.

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