Modulation of Amyloid β-induced Microglia Activation and Neuronal Cell Death by Curcumin and Analogues

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is not restricted to the neuronal compartment but includes important interactions with immune cells, including microglia. Protein aggregates, common pathological hallmarks of AD, bind to pattern recognition receptors on microglia and trigger an inflammatory response, which contributes to disease progression and severity. In this context, curcumin is emerging as a potential drug candidate able to affect multiple key pathways implicated in AD, including neuroinflammation. Therefore, we studied the effect of curcumin and its structurally related analogues cur6 and cur16 on amyloid-beta (A beta)-induced microglia activation and neuronal cell death, as well as their effect on the modulation of A beta aggregation. Primary cortical microglia and neurons were exposed to two different populations of A beta 42 oligomers (A beta 42Os) where the oligomeric state had been assigned by capillary electrophoresis and ultrafiltration. When stimulated with high molecular weight A beta 42Os, microglia released proinflammatory cytokines that led to early neuronal cell death. The studied compounds exerted an anti-inflammatory effect on high molecular weight A beta 42O-stimulated microglia and possibly inhibited microglia-mediated neuronal cell toxicity. Furthermore, the tested compounds demonstrated antioligomeric activity during the process of in vitro A beta 42 aggregation. These findings could be investigated further and used for the optimization of multipotent candidate molecules for AD treatment.