The butyrylcholinesterase K variant confers structurally-derived risks for Alzheimer's pathology.
J Biol Chem. 2009 Apr 21;
Authors: Podoly E, Shalev DE, Shenhar-Tsarfaty S, Bennett ER, Ben Assayag E, Wilgus H, Livnah O, Soreq H
The K variant of butyrylcholinesterase (BChE-K, 20% incidence) is a long-debated risk factor for Alzheimer's 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 compared to "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 inter-molecular 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 hence account for both neuroprotective characteristics caused by sustained acetylcholine levels, and elevated AD risk due to inefficient interference with amyloidogenic processes.
PMID: 19383604 [PubMed - as supplied by publisher]