Interactions of AChE with A? Aggregates in Alzheimer?s Brain: Therapeutic Relevance of IDN 5706

Abstract

Acetylcholinesterase (AChE; EC 3.1.1.7) plays a crucial role in the rapid hydrolysis of the neurotransmitter acetylcholine, in the central and peripheral nervous system and might also participate in non-cholinergic mechanism related to neurodegenerative diseases. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β (Aβ) peptide accumulation and synaptic alterations. We have previously shown that AChE is able to accelerate the Aβ peptide assembly into Alzheimer-type aggregates increasing its neurotoxicity. Furthermore, AChE activity is altered in brain and blood of Alzheimer’s patients. The enzyme associated to amyloid plaques changes its enzymatic and pharmacological properties, as well as, increases its resistant to low pH, inhibitors and excess of substrate. Here, we reviewed the effects of IDN 5706, a hyperforin derivative that has potential preventive effects on the development of AD. Our results show that treatment with IDN 5706 for 10 weeks increases brain AChE activity in 7-month-old double transgenic mice (APPSWE–PS1) and decreases the content of AChE associated with different types of amyloid plaques in this Alzheimer’s model. We concluded that early treatment with IDN 5706 decreases AChE–Aβ interaction and this effect might be of therapeutic interest in the treatment of AD.

Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

“…AChE possesses two binding sites: the catalytic active site (CAS) that is located at the bottom of a 20 Å gorge responsible for neurotransmitter hydrolysis, and the peripheral anionic site (PAS) that is rich in aromatic residues located at the rim of the gorge on the surface of the enzyme. 4 The noncholinergic functions of AChE are directly related to the PAS of the enzyme. However, even after many studies, the precise function and pathological mechanism of PAS inhibition still remains unclear, especially its role in the progress of Aβ formation.…”

Targeting Assembly and Disassembly of Protein Aggregates

“…As its parent compound, THP alleviates the consequences of Ab aggregate-dependent pathologies by, inter alia, disrupting the AChE-Ab interaction and disassembling pre-formed Ab aggregates [226]. It alleviates Ab-induced memory decline, decreases the levels of larger size Ab deposits, and prevents astroglyosis and oxidative damage triggered by high Ab deposit levels in 12-month-old double Sweden-APP, ∆E9-PSEN1 TG mice (2 mg/kg p.o.…”

Molecular perception of interactions between bis(7)tacrine and cystamine-tacrine dimer with cholinesterases as the promising proposed agents for the treatment of Alzheimer’s disease

“…This process is called AChE-induced Aβ aggregation. Therefore, simultaneous inhibition of the active site and peripheral anionic site with suitable dual inhibitors can prevent acetylcholine degradation and accumulation of beta amyloid monomers (Alvarez et al, 1997;Carvajal & Inestrosa, 2011).…”