Article

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

Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile Santiago, Chile.
Frontiers in Molecular Neuroscience (Impact Factor: 4.08). 09/2011; 4:19. DOI: 10.3389/fnmol.2011.00019
Source: PubMed

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 (APP(SWE)-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.

  • Source
    • "To get more insight about these dual and apparently counteracting effects, we examined whether the latter was due to donepezil molecule-preventing interaction of A␤ with AChE, putatively by competing for PAS on AChE protein [45]. Therefore, we measured changes in the AChE activity in the CSF samples, before and after addition and incubation (>72 hours) with recombinant A␤ peptides. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite three decades of intensive research in the field of Alzheimer's disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-β peptide (Aβ) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced Aβ aggregation, most likely by competing with the Aβ peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between Aβ and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders.
    Full-text · Article · Nov 2013 · Journal of Alzheimer's disease: JAD
  • Source
    • "There seems to be a synergistic effect to improve learning and memory deficits in rats by co-administration of Icariin and Panax notoginseng saponins [676]. IDN-5706, a hyperforin derivative, decreased the content of acetylcholinesterase associated with different types of A␤ plaques in 7-month-old double A␤PP SWE /PS1 transgenic mice after treatment with IDN 5706 for 10 weeks [677]. Kaempferol protected PC12 and T47D cells from A␤ toxicity [581] [678] [679]. "

    Full-text · Dataset · Apr 2013
  • Source
    • "There seems to be a synergistic effect to improve learning and memory deficits in rats by co-administration of Icariin and Panax notoginseng saponins [676]. IDN-5706, a hyperforin derivative, decreased the content of acetylcholinesterase associated with different types of A␤ plaques in 7-month-old double A␤PP SWE /PS1 transgenic mice after treatment with IDN 5706 for 10 weeks [677]. Kaempferol protected PC12 and T47D cells from A␤ toxicity [581] [678] [679]. "

    Full-text · Dataset · Apr 2013
Show more