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

Abstract

Amyloid β 1–42 (Aβ1–42) 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 Aβ1–42 toxicity. By performing the Thioflavin T fluorescence assay, Western blotting analyses, and Circular Dichroism experiments, we found that ISOAC1 was able to reduce the Aβ1–42 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 Aβ1–42, establishing a hydrophobic interaction with the PHE19 residue of the Aβ1–42 KLVFF motif. In vitro analyses on primary cortical neurons showed that ISOAC1 counteracted the increase of intracellular Ca2+ levels and decreased the Aβ1–42-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 Aβ1–42 intraneuronal accumulation. Collectively, our results clearly show that ISOAC1 exerts a neuroprotective effect by reducing the Aβ1–42 aggregation and toxicity, hence emerging as a promising compound for the development of new Aβ-targeting therapeutic strategies for AD treatment.

Keywords

• β-diketone-3-substituted isoindolinone
• Amyloid β 1–42 aggregation
• Alzheimer’s disease
• Neuroprotection