Protection against Alzheimer's disease by luteolin: Role of brain glucose regulation, anti‐inflammatory activity, and the gut microbiota‐liver‐brain axis

Luteolin is a widely distributed flavone herbs and vegetables. It has anti-oxidant and anti-inflammatory activities and improves glucose metabolism by potentiating insulin sensitivity and improving β-cell function and mass. Alzheimer's disease (AD) is induced by the deposition of amyloid-beta (Aβ) in the hippocampus and the formation of neurotoxic Aβ plaques. The Aβ deposition is associated with increased formation of Aβ from amyloid precursor protein by up-regulation of β-secretase and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1). Furthermore, Aβ accumulation is increased by brain insulin resistance. The impairment of insulin/IGF-1 signaling mainly in the hippocampus and brain insulin resistance is connected to signals originating in the liver and gut microbiota, known as the gut microbiota-liver-brain axis. This indicates that the changes in the production of short-chain fatty acids by the gut microbiota and pro-inflammatory cytokines can alter insulin resistance in the liver and brain. Luteolin is detected in the brain tissues after passing through the blood-brain barrier, where it can directly influence neuroinflammation and brain insulin resistance and modulate Aβ deposition. Luteolin (10-70 mg/kg bw for rodents) can modulate the systemic and brain insulin resistance, and it suppresses AD development directly, and it influences Aβ deposition by activation of the gut microbiota-liver-brain axis. In this review, we evaluate the potential of luteolin to mitigate two potential causes of AD, neuroinflammatory processes, and disruption of glucose metabolism in the brain. This review suggests that luteolin intake can enhance brain insulin resistance and neuroinflammation, directly and indirectly, to protect against the development of Alzheimer's-like disease, and the gut microbiota-liver-brain axis is mainly involved in the indirect pathway. However, most studies have been conducted in animal studies, and human clinical trials are needed.