The butyrylcholinesterase K variant confers structurally derived risks for Alzheimer pathology

Erez Podoly, Deborah E. Shalev, Shani Shenhar-Tsarfaty, Estelle R. Bennett, Einor Ben Assayag, Harvey Wilgus, Oded Livnah, Hermona Soreq*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


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 β-amyloid (Aβ) 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 Aβ oligomerization than its BSP-U counterpart. Correspondingly, highly purified recombinant human rBChE-U monomers suppressed β-amyloid fibril formation less effectively than dimers, which also protected cultured neuroblastoma cells from Aβ 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.

Original languageAmerican English
Pages (from-to)17170-17179
Number of pages10
JournalJournal of Biological Chemistry
Issue number25
StatePublished - 19 Jun 2009


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