TLR4/NF-κB-Mediated Anti-Inflammatory and Cognitive Protective Actions of Curcuma longa and Ar-turmerone in Alzheimer's Disease Models.

In our previous study, we systematically compared various extraction methods and identified the 80% ethanolic extract of Curcuma longa L. (CL-80) as the most effective in protecting neurons from stress-induced damage in both in vitro and in vivo models. Although curcumin, a major constituent of C. longa, has demonstrated neuroprotective effects, the role of ar-turmerone, a bioactive sesquiterpenoid also derived from C. longa, remains underexplored in Alzheimer's disease (AD) models. In this study, we evaluated the anti-inflammatory and cognitive-protective effects of CL-80 and ar-turmerone in both in vitro and in vivo models of amyloid-β (Aβ)-induced neurotoxicity. Primary cultured rat hippocampal neurons exposed to Aβ_25-35 showed significantly increased expression of TNF-α, IFN-β, and iNOS, all of which were dose-dependently attenuated by CL-80 or ar-turmerone. Furthermore, both compounds suppressed Aβ-induced activation of the TLR4/NF-κB signaling axis at mRNA and protein levels. In an Aβ_1-42-injected mouse model, oral administration of CL-80 or ar-turmerone significantly improved learning and memory performance in the Morris water maze and passive avoidance tests. Biochemical analyses of hippocampal tissues revealed reduced TLR4 expression and NF-κB activation, decreased acetylcholinesterase (AChE) activity, and restoration of acetylcholine (ACh) levels following treatment. Collectively, these findings suggest that both CL-80 and ar-turmerone exert neuroprotective effects by inhibiting TLR4/NF-κB-mediated neuroinflammation and preserving cholinergic function in an AD animal model. This study offers novel insight into the therapeutic potential of C. longa constituents for the treatment of AD.