4.7 Review

An Overview of Several Inhibitors for Alzheimer's Disease: Characterization and Failure

Journal

Publisher

MDPI
DOI: 10.3390/ijms221910798

Keywords

Alzheimer's disease; amyloid beta peptide; plaque formation; small molecules; M30; gabapentin; MD simulation

Funding

  1. Direccion General de Asuntos del Personal Academico de la Universidad Nacional Autonoma de Mexico (DGAPA-UNAM)
  2. National Science Centre, Poland [2017/26/D/NZ1/00466]
  3. Foundation for Polish Science [MAB PLUS/11/2019]

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Understanding the aggregation and toxicity pathways of Aβ oligomers is crucial for developing therapeutic strategies for Alzheimer's disease, computer simulation can aid experimental studies in mapping the generation mechanism of Aβ, and currently there is no good drug candidate available for clinical treatment.
Amyloid beta (A beta) oligomers are the most neurotoxic aggregates causing neuronal death and cognitive damage. A detailed elucidation of the aggregation pathways from oligomers to fibril formation is crucial to develop therapeutic strategies for Alzheimer's disease (AD). Although experimental techniques rely on the measure of time- and space-average properties, they face severe difficulties in the investigation of A beta peptide aggregation due to their intrinsically disorder character. Computer simulation is a tool that allows tracing the molecular motion of molecules; hence it complements A beta experiments, as it allows to explore the binding mechanism between metal ions and A beta oligomers close to the cellular membrane at the atomic resolution. In this context, integrated studies of experiments and computer simulations can assist in mapping the complete pathways of aggregation and toxicity of A beta peptides. A beta oligomers are disordered proteins, and due to a rapid exploration of their intrinsic conformational space in real-time, they are challenging therapeutic targets. Therefore, no good drug candidate could have been identified for clinical use. Our previous investigations identified two small molecules, M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine) and Gabapentin, capable of A beta binding and inhibiting molecular aggregation, synaptotoxicity, intracellular calcium signaling, cellular toxicity and memory losses induced by A beta. Thus, we recommend these molecules as novel candidates to assist anti-AD drug discovery in the near future. This review discusses the most recent research investigations about the A beta dynamics in water, close contact with cell membranes, and several therapeutic strategies to remove plaque formation.

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