Butyrylcholinesterase attenuates amyloid fibril formation in vitro

Abstract

In Alzheimer's disease, both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) colocalize with brain fibrils of amyloid-␤ (A␤) peptides, and synaptic AChE-S facilitates fibril formation by association with insoluble A␤ fibrils. Here, we report that human BChE and BSP41, a synthetic peptide derived from the BChE C terminus, inversely associate with the soluble A␤ conformers and delay the onset and decrease the rate of A␤ fibril formation in vitro, at a 1:100 BChE͞A␤ 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 A␤ 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 ␣-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.

Human Recombinant Butyrylcholinesterase Purified from the Milk of Transgenic Goats Interacts with Beta-Amyloid Fibrils and Suppresses Their Formation in vitro

“…Samples were incubated (20 min, room temperature) and 80 l of 1.25 M ThT working solution were added. Fibril formation kinetics was monitored continuously using an automated fluorescent plate reader (Tecan, Research Triangle Park, N.C., USA; excitation, 450 nm; emission, 485 nm; 30 ° C; 20 h; reading intervals, 15 min; samples mixed for 5 min prior to each reading cycle) [15] .…”

“…We have recently demonstrated that human serumderived BChE and synthetic peptides derived from its C-terminus can actively attenuate fibril formation in vitro [15] . However, supply capacities and health risks limit the value of serum-derived proteins in general.…”

Kinetics of Human Serum Butyrylcholinesterase Inhibition by a Novel Experimental Alzheimer Therapeutic, Dihydrobenzodioxepine Cymserine

“…AChE-Is (donepezil) and ChE-Is (rivastigmine and galantamine) are currently the mainstay of AD treatment, but induce dose-limiting adverse effects [5]. Hence, selective BuChE inhibition thereby represents an interesting new strategy to ameliorate AD, particularly since BuChE readily cleaves ACh and co-localizes in high amounts with the classical pathological hallmarks of AD and may be involved in the molecular events underpinning disease progression [1,2,15,16].…”

The diabetic brain and cognition

“…Alterations in the level of plasma BChE occur in DM; variant forms of the plasma enzyme occur in both DM and AD (Sridhar et al 2010;Raygani et al 2004). In vitro studies demonstrate a common pathogenic mechanism (Sridhar et al 2006;Diamant et al 2006). Whereas brain hyperglycemia mediates hippocampal neuron responses (Macauley et al 2015), BCHE levels also correlate with cerebral glucose metabolism and cerebral Ab load (Darreh-Shori et al 2011).…”