The butyrylcholinesterase K variant confers structurally derived risks for Alzheimer pathology.
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.
Podoly
Erez
E
From The Alexander Silberman Life Sciences Institute, Jerusalem 91904, Israel; The Wolfson Centre for Applied Structural Biology, Safra Campus Givat Ram, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Shalev
Deborah E
DE
The Wolfson Centre for Applied Structural Biology, Safra Campus Givat Ram, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Shenhar-Tsarfaty
Shani
S
Department of Neurology, Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 69978, Israel.
Bennett
Estelle R
ER
From The Alexander Silberman Life Sciences Institute, Jerusalem 91904, Israel.
Ben Assayag
Einor
E
Department of Neurology, Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 69978, Israel.
Wilgus
Harvey
H
PharmAthene Canada Inc., Montreal, Quebec QC H4S 2C8, Canada.
Livnah
Oded
O
From The Alexander Silberman Life Sciences Institute, Jerusalem 91904, Israel; The Wolfson Centre for Applied Structural Biology, Safra Campus Givat Ram, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Soreq
Hermona
H
From The Alexander Silberman Life Sciences Institute, Jerusalem 91904, Israel. Electronic address: soreq@cc.huji.ac.il.
D000368:Aged; D000544:Alzheimer Disease / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D001483:Base Sequence; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
D016229:Amyloid beta-Peptides; D017931:DNA Primers; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D002091:Butyrylcholinesterase