Characterization of the biological effect of new molecules as potential therapeutic agents for Alzheimer's disease

Alzheimer's disease is the most prevalent form of dementia in elderly, presenting a significant global public health challenge. Its pathological hallmarks include extracellular amyloid β (Aβ) aggregates or senile plaques, intracellular neurofibrillary tangles, and inflammatory processes. Despite recent therapeutic approvals targeting Aβ, controversies persist regarding their efficacy. Our goal is to determine the biological impact of molecules that inhibit various steps of Alzheimer's development, which could potentially be integrated into complex treatment regimens in the future. To this end, we assessed the effects of four synthetic molecules, derived from quinolines, on amyloid aggregation and inflammatory responses from macrophage and microglia cell lines exposed to Aβ42 fibrils. Amyloid aggregation inhibition was evaluated using the Thioflavin T method, while molecular dynamics elucidated compound interactions with different amyloid species. Anti-inflammatory effect was determined by evaluating the inhibition of the expression and production of inflammatory mediators induced by Aβ42. Flow cytometry was used to assess the compound impact on Aβ42 uptake. Of the tested molecules, all except one inhibited amyloid aggregation, as confirmed by in silico analyses. Notably, only one of the three with anti-aggregation effect, suppressed the inflammatory response in macrophages and microglia to Aβ42, without affecting the response to LPS, suggesting an apparent specificity. This molecule had also an impact on amyloid uptake. Our results identified a potential candidate for further investigation in primary cell lines and in vivo models, indicating promising avenues for future research.