Abstract

In Alzheimer's disease (AD), native A beta protein monomers aggregate through the formation of a variety of water-soluble, toxic oligomers, ultimately leading to insoluble fibrillar deposits. The inhibition of oligomers formation and/or their dissociation into non-toxic monomers, are considered an attractive strategy for the prevention and treatment of AD. A number of studies have demonstrated that small molecules, containing single or multiple (hetero)aromatic rings, can inhibit protein aggregation, being potentially effective in AD treatment.Starting from previously reported data on the antiamyloidogenic activity of a series of 3-hydrazonoindolinones, compound PT2 was selected to deeply investigate the inhibitory mechanism in the A beta aggregation cascade. We compared data from DLS, NMR, CD, TEM and ThT fluorescence measures to ascertain the interactions with amyloidogenic species formed in vitro during the aggregation process, and confirmed this feature with cell viability tests on HeLa cultured cells. PT2 was effective in disrupting toxic oligomers and mature amyloid fibrils, stabilizing A beta as non-toxic, beta-sheet arranged, ThT-insensitive protofilaments. It also strongly reduced cellular toxicity caused by A beta and showed good antioxidant properties in two radical scavenging tests. Taken together, these data confirmed that PT2 is a small molecule inhibitor of A beta oligomerization and toxicity, displaying also additional activity as antioxidant.

Autore Pugliese

• De Stradis Angelo

Tutti gli autori

• Catto M.; Arnesano F.; Palazzo G.; De Stradis A.; Calò V.; Losacco M.; Purgatorio R.; Campagna F.

Titolo volume/Rivista

Archives of biochemistry and biophysics

Anno di pubblicazione

2014

ISSN

0003-9861

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

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Numero di citazioni Scopus

Non Disponibile

Ultimo Aggiornamento Citazioni

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Settori ERC

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Codici ASJC

Non Disponibile