Neuromodulation with low-intensity pulsed ultrasound (Lipus) combined with curcumin-gold nanoparticles (Cur-AuNPs) in an Alzheimer's disease model

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that requires innovative therapeutic strategies. This is the first study to evaluate the synergistic effects of LIPUS and CUR-AuNPs in an AD model, which aimed to investigate the effects of these therapies on learning, memory and neuroinflammation in mice with β-amyloid peptide (βA1−42)-induced AD. Sixty mice were divided into five groups: control, βA1−42, βA1−42 + LIPUS, βA1−42 + CUR-AuNPs, and βA1−42 + LIPUS + CUR-AuNPs. Treatments began 24 hours after induction and continued for 17 days using intranasal CUR-AuNPs (25  μg/mL) and transcranial LIPUS (0.8 W/cm², 1 MHz). The results demonstrated that the isolated therapies reversed memory deficits in the Y-maze and radial maze tests. However, the combined therapy group was able to reverse these deficits only in the radial maze. Electron microscopy confirmed the ability of CUR-AuNPs to cross the blood‒brain barrier, especially in the combined group, and no liver toxicity was observed. All the treated groups presented increased BDNF in the hippocampus and cortex. IL-1β and IL-6 levels are reduced in the cortex, while IL-1β and TNF-α levels are decreased in the hippocampus. IL-10 increased only in the hippocampus, while GSH levels increased in both regions. Combination therapy also reduced nitrite concentrations in the hippocampus and cortex and NFκB expression in the hippocampus. APP expression decreased exclusively in the LIPUS group in the hippocampus. These results suggest that although single treatments are effective, their combination enhances neuroprotective responses through the modulation of inflammation, oxidative stress, and neurotrophic signaling, suggesting promising potential for AD treatment.
Schematic representation of blood‒brain barrier (BBB) opening mediated by microbubbles through the cavitation effect of low-intensity pulsed ultrasound (LIPUS) to facilitate the delivery of CUR-AuNPs to the brain. LIPUS application induces cavitation and the formation of bubbles around the tissue, resulting in vessel wall displacement and the transient, safe opening of tight junctions in the BBB. This temporary opening allows CUR-AuNPs to cross the barrier and contribute to amyloid plaque degradation. The magnified insets illustrate the structure of tight junctions under normal conditions (left) and after ultrasound application (right), highlighting the roles of junctional proteins such as occludin, claudin-5, and ZO-1, as well as the efflux transporter protein P-gp.