Brain-targeted lycopene-loaded microemulsion modulates neuroinflammation, oxidative stress, apoptosis and synaptic plasticity in β-amyloid-induced Alzheimer's disease mice

Objectives: beta-Amyloid protein (A beta) plays pivotal roles in pathogenesis of Alzheimer's disease (AD) and triggers various pathophysiological events. Lycopene is a promising neuroprotector with multiple bioactivities, while its bioavailability is limited. Lycopene-loaded microemulsion (LME) possessing superior bioavailability and brain-targeting efficiency was developed in our previous study. In this investigation, we aimed to comprehensively evaluate its neuroprotective effects and underlying mechanisms using intracerebroventricular (ICV) A beta(1-42) injection mice. Methods: Mice were assigned to the Sham, A beta, A beta + LME and A beta + lycopene dissolved in olive oil (LOO) groups. ICV A beta(1-42) administration was performed, followed by oral gavage of brain-targeted LME or conventional LOO formulation for 3 weeks. Brain samples were harvested for immunohistochemistry, biochemical assays and western blotting analyses. Results: Our findings verified A beta-induced neurotoxicity on neuroinflammation, oxidative stress, apoptosis, A beta metabolisms and synaptic plasticity. LME supplementation dramatically attenuated astrocytosis and microgliosis, decreased malondialdehyde production and rescued antioxidant capacities, normalized apoptotic parameters and alleviated neuronal loss, inhibited amyloidogenic processing and activated non-amyloidogenic pathway, together with upregulating synaptic protein expressions and restoring synaptic plasticity. Nevertheless, most of these phenomena were not observed for mice treated with LOO, implying that LME showed significantly higher therapeutic efficacy against A beta injury. Discussion: In summary, brain-targeted LME could exert neuroprotective function via suppressing a series of cascades triggered by A beta aggregates, thus ameliorating A beta neurotoxicity and associated abnormalities. Given this, LME may serve as an attractive candidate for AD prevention and treatment, and superiority of brain-targeting delivery is highlighted.