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Disease-modifying anti-Alzheimer's drugs: inhibitors of human cholinesterases interfering with ?-amyloid aggregation.

ABSTRACT: AIMS:We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with A? aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level. METHODS:We determined the inhibitory potency of 2a-c on A?1-42 self-aggregation, the interference of 2a with the toxic A? oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of A? toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with A? and with the A?-preformed fibrils were computationally analyzed. 2a-c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts). RESULTS:Our prototypical pluripotent analogue 2a interferes with A? oligomerization process thus reducing A? oligomers-mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a. CONCLUSION:Converging analytical, biological, and in silico data explained the mechanism of action of 2a on A?1-42 oligomers formation and against A?-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.

SUBMITTER: Brogi S

PROVIDER: S-EPMC6493034 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Disease-modifying anti-Alzheimer's drugs: inhibitors of human cholinesterases interfering with β-amyloid aggregation.

Brogi Simone S Butini Stefania S Maramai Samuele S Colombo Raffaella R Verga Laura L Lanni Cristina C De Lorenzi Ersilia E Lamponi Stefania S Andreassi Marco M Bartolini Manuela M Andrisano Vincenza V Novellino Ettore E Campiani Giuseppe G Brindisi Margherita M Gemma Sandra S

CNS neuroscience & therapeutics 20140701 7

<h4>Aims</h4>We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with Aβ aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level.<h4>Methods</h4>We determined the inhibitory potency of 2a-c on Aβ1-42 self-aggregation, the interference of 2a with the toxic Aβ oligomeric species and with the postaggregation stat ...[more]

PMID: 24935788

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Project description:The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases caused by the abnormal expansion of a CAG trinucleotide repeat that are translated into an expanded polyQ stretch in the disease-causative proteins. The expanded polyQ stretch itself plays a critical disease-causative role in the pathomechanisms underlying polyQ diseases. Notably, the expanded polyQ stretch undergoes a conformational transition from the native monomer into the ?-sheet-rich monomer, followed by the formation of soluble oligomers and then insoluble aggregates with amyloid fibrillar structures. The intermediate soluble species including the ?-sheet-rich monomer and oligomers exhibit substantial neurotoxicity. Therefore, protein conformation stabilization and aggregation inhibition that target the upstream of the insoluble aggregate formation would be a promising approach toward the development of disease-modifying therapies for polyQ diseases. PolyQ aggregation inhibitors of different chemical categories, such as intrabodies, peptides, and small chemical compounds, have been identified through intensive screening methods. Among them, recent advances in the brain delivery methods of several peptides and the screening of small chemical compounds have brought them closer to clinical utility. Notably, the recent discovery of arginine as a potent conformation stabilizer and aggregation inhibitor of polyQ proteins both in vitro and in vivo have paved way to the clinical trial for the patients with polyQ diseases. Meanwhile, expression reduction of expanded polyQ proteins per se would be another promising approach toward disease modification of polyQ diseases. Gene silencing, especially by antisense oligonucleotides (ASOs), have succeeded in reducing the expression of polyQ proteins in the animal models of various polyQ diseases by targeting the aberrant mRNA with expanded CAG repeats. Of note, some of these ASOs have recently been translated into clinical trials. Here we overview and discuss these recent advances toward the development of disease modifying therapies for polyQ diseases. We envision that combination therapies using aggregation inhibitors and gene silencing would meet the needs of the patients with polyQ diseases and their caregivers in the near future to delay or prevent the onset and progression of these currently intractable diseases.

Dataset Information

Disease-modifying anti-Alzheimer's drugs: inhibitors of human cholinesterases interfering with ?-amyloid aggregation.

Publications

Disease-modifying anti-Alzheimer's drugs: inhibitors of human cholinesterases interfering with β-amyloid aggregation.

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