A Structural Motif of Acetylcholinesterase That Promotes Amyloid β-Peptide Fibril Formation

Abstract

Acetylcholinesterase (AChE) has been found to be associated with the core of senile plaques. We have shown that AChE interacts with the amyloid beta-peptide (Abeta) and promotes amyloid fibril formation by a hydrophobic environment close to the peripheral anionic binding site (PAS) of the enzyme. Here we present evidence for the structural motif of AChE involved in this interaction. First, we modeled the docking of Abeta onto the structure of Torpedo californica AChE, and identified four potential sites for AChE-Abeta complex formation. One of these, Site I, spans a major hydrophobic sequence exposed on the surface of AChE, which had been previously shown to interact with liposomes [Shin et al. (1996) Protein Sci. 5, 42-51]. Second, we examined several AChE-derived peptides and found that a synthetic 35-residue peptide corresponding to the above hydrophobic sequence was able to promote amyloid formation. We also studied the ability to promote amyloid formation of two synthetic 24-residue peptides derived from the sequence of a Omega-loop, which has been suggested as an AChE-Abeta interacting motif. Kinetic analyses indicate that only the 35-residue hydrophobic peptide mimics the effect of intact AChE on amyloid formation. Moreover, RP-HPLC analysis revealed that the 35-residue peptide was incorporated into the growing Abeta-fibrils. Finally, fluorescence binding studies showed that this peptide binds Abeta with a K(d) = 184 microM, independent of salt concentration, indicating that the interaction is primarily hydrophobic. Our results indicate that the homologous human AChE motif is capable of accelerating Abeta fibrillogenesis.

Multifunctional Cholinesterase and Amyloid Beta Fibrillization Modulators. Synthesis and Biological Investigation

“…It is worthy of note that these moieties, although solvent exposed, lay in close proximity to P283 and F284 (Figure 2 bottom panels B−C), which have already been identified as relevant for binding Aβ. 8 This evidence is in line with the higher experimentally determined potency of 2b,c in inhibiting hAChE induced Aβ aggregation with respect to 2a. As shown in Figure 3, the peptidic aromatic groups of 2b,c may physically hamper Aβ binding to the surface of the enzyme.…”

Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents

“…[11][12][13][14][15] Multi-target compounds have been usually designed to hit at least Aβ formation and aggregation and AChE activity, 16 especially prompted by the finding that AChE can bind Aβ, thereby promoting its aggregation and increasing its neurotoxicity. [17][18][19] The recognition site of Aβ within AChE is the so-called peripheral anionic site (PAS) and it is located at the entrance of a 20 Å deep narrow gorge that leads to the catalytic anionic site (CAS). 20 The design of inhibitors able to simultaneously reach both sites of AChE, i.e.…”

Shogaol–huprine hybrids: Dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties

“…Some classes of AChE inhibitors, especially dual binding site inhibitors, are often endowed with Aβ anti-aggregating properties, 38 which arise either from blockade of the AChE peripheral anionic site (PAS) (blockade of AChE-induced Aβ aggregation) [39][40][41] or from a direct interaction with Aβ (blockade of spontaneous Aβ aggregation), in the latter case likely due to the presence of aromatic planar moieties in the inhibitors.…”