The 3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1) as a new molecule able to inhibit Amyloid β aggregation and neurotoxicity.

Amyloid β 1–42 (Aβ 1–42) protein aggregation is considered one of the main triggers of Alzheimer's disease (AD). In this study, we examined the in vitro anti-amyloidogenic activity of the isoindolinone derivative 3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1) and its neuroprotective potential against the Aβ 1–42 toxicity. By performing the Thioflavin T fluorescence assay, Western blotting analyses, and Circular Dichroism experiments, we found that ISOAC1 was able to reduce the Aβ 1–42 aggregation and conformational transition towards β-sheet structures. Interestingly, in silico studies revealed that ISOAC1 was able to bind to both the monomer and a pentameric protofibril of Aβ 1–42 , establishing a hydrophobic interaction with the PHE19 residue of the Aβ 1–42 KLVFF motif. In vitro analyses on primary cortical neurons showed that ISOAC1 counteracted the increase of intracellular Ca2+ levels and decreased the Aβ 1–42 -induced toxicity, in terms of mitochondrial activity reduction and increase of reactive oxygen species production. In addition, confocal microscopy analyses showed that ISOAC1 was able to reduce the Aβ 1–42 intraneuronal accumulation. Collectively, our results clearly show that ISOAC1 exerts a neuroprotective effect by reducing the Aβ 1–42 aggregation and toxicity, hence emerging as a promising compound for the development of new Aβ-targeting therapeutic strategies for AD treatment. [Display omitted] • ISOAC1 inhibits the Amyloid β 1–42 (Aβ 1–42) aggregation and conformational transition to β-sheet structures. • ISOAC1 reduces the neurotoxicity of Aβ 1–42 aggregates. • ISOAC1 interacts with the PHE19 residue of both monomeric and protofibrillar Aβ 1–42. • ISOAC protects primary cortical neurons from Aβ 1–42 toxicity. [ABSTRACT FROM AUTHOR]