New low-dose curcumin derivative with therapeutic potential in Alzheimer’s disease: Results from an in vitro and in vivo study in mice

• Published in: Neurobiology of aging 2025-03, Vol.147, p.105-123
• Main Authors: Rodrigues, Beatriz, Ventura, Eduarda, Moreira, Patrícia, Resende, Rosa, Bicker, Joana, Santos, Armanda E., Pereira, Cláudia Fragão, Cruz, Maria Teresa, Robalo, Maria Paula, Silva, Ana, Silva, Sónia
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Cognitive function; Curcumin derivative; Neuroinflammation; Nrf2 activation; Oxidative Stress; Transgenic mice APP/PS1
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2024.12.005

Curcumin has been proposed as a potential treatment for Alzheimer’s disease (AD) due to its ability to inhibit amyloid-β (Aβ) peptide aggregates and to destabilise pre-formed ones. Derivative 27 was synthesized to improve low-dose efficacy in the context of AD. Its anti-inflammatory, antioxidant and anti-amyloidogenic activities were evaluated in chemico, in vitro using AD and neuroinflammation cell models, and in vivo using the double-transgenic APP/PS1 mice. In vitro, this curcumin derivative significantly reduced nitric oxide (NO) production and levels of pro-inflammatory proteins, inducible NO synthase, pro-interleukin-1β (Pro-IL-1β) and cyclooxygenase-2. Furthermore, Derivative 27 activated nuclear factor erythroid 2-related factor 2 transcription factor (Nrf2) and significantly increased Nrf2 and heme-oxygenase-1 protein levels in the nucleus and in the cytoplasm, respectively. In one-year-old APP/PS1 mice, orally administered-Derivative 27 (50 mg/Kg/day) for 28 days improved spatial short-term memory and significantly decreased hippocampal Pro-IL-1β and amyloid precursor protein levels, as well as Aβ levels in the hippocampus and plasma. This study supports developing new chemical approaches to alter curcumin molecule, enabling lower doses, while increasing the effectiveness in AD treatment. [Display omitted] •Derivative 27 is a curcumin derivative with increased efficacy at low doses.•It has significant in chemico inhibitory activity against BACE1.•It has significant in vitro anti-inflammatory and antioxidant effects.•In vivo, it prevents short-term spatial memory decline.•It decreases APP and Aβ peptides levels in hippocampus and plasma, in vivo.•It decreases in vivo Pro-IL-1β levels in the hippocampus and secreted IL-1β.