Butyrylcholinesterase attenuates amyloid fibril formation in vitro.
In Alzheimer's disease, both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) colocalize with brain fibrils of amyloid-beta (Abeta) peptides, and synaptic AChE-S facilitates fibril formation by association with insoluble Abeta fibrils. Here, we report that human BChE and BSP41, a synthetic peptide derived from the BChE C terminus, inversely associate with the soluble Abeta conformers and delay the onset and decrease the rate of Abeta fibril formation in vitro, at a 1:100 BChE/Abeta molar ratio and in a dose-dependent manner. The corresponding AChE synthetic peptide (ASP)40 peptide, derived from the homologous C terminus of synaptic human (h)AChE-S, failed to significantly affect Abeta fibril formation, attributing the role of enhancing this process to an AChE domain other than the C terminus. Circular dichroism and molecular modeling confirmed that both ASP40 and BChE synthetic peptide (BSP)41 are amphipathic alpha-helices. However, ASP40 shows symmetric amphipathicity, whereas BSP41 presented an aromatic tryptophan residue in the polar side of the C terminus. That this aromatic residue is causally involved in the attenuating effect of BChE was further supported by mutagenesis experiments in which (W8R) BSP41 showed suppressed capacity to attenuate fibril formation. In Alzheimer's disease, BChE may have thus acquired an inverse role to that of AChE by adopting imperfect amphipathic characteristics of its C terminus.
Diamant
Sophia
S
Department of Biological Chemistry, Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.
Podoly
Erez
E
Friedler
Assaf
A
Ligumsky
Hagai
H
Livnah
Oded
O
Soreq
Hermona
H
D000110:Acetylcholinesterase / Q000737:chemistry; D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D017124:Conserved Sequence; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship
D000682:Amyloid; D010455:Peptides; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase