The potential of synthetic indolylquinoline derivatives for Aβ aggregation reduction by chemical chaperone activity

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia associated with progressive cognitive decline and memory loss. Extracellular β-amyloid (Aβ) is a major constituent of senile plaques, one of the pathological hallmarks of AD. Aβ deposition causes neuronal death via a number of possible mechanisms such as increasing oxidative stress. Therefore therapeutic approaches to identify novel Aβ aggregate reducers could be effective for AD treatment. Using a Trx-His-Aβ biochemical assay, we screened 11 synthetic indolylquinoline compounds, and found NC009-1, -2, -6 and -7 displaying potential to reduce Aβ aggregation. Treating Tet-On Aβ-GFP 293 cells with these compounds reduced Aβ aggregation and reactive oxygen species. These compounds also promoted neurite outgrowth in Tet-On Aβ-GFP SH-SY5Y cells. Furthermore, treatment with above compounds improved neuronal cell viability, neurite outgrowth, and synaptophysin expression level in mouse hippocampal primary culture under oligomeric Aβ-induced cytotoxicity. Moreover, the tested NC009-1 significantly ameliorated Aβ-induced inhibition of hippocampal long-term potentiation in mouse hippocampal slices. Our results demonstrate how synthetic indolylquinoline compounds are likely to work as chemical chaperones in Aβ-aggregation reduction and neuroprotection, providing insight into the possible applications of indolylquinoline compounds in AD treatment.

Keywords: Alzheimer's disease; Aβ aggregation; Synthetic indolylquinoline derivatives; Therapeutics.