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Alzheimer’s disease (AD) is a neurodegenerative disease with a high incidence in the elderly. Many preclinical studies show that a natural product, ferulic acid (FA), displays neuroprotective effects in AD models. This review aims to systematically review and meta-analyze published pre-clinical researches about the effects, mechanism, and clinical prospects of FA in the treatment of AD. According to the pre-determined search strategy and inclusion criteria, a total of 344 animals in 12 papers were included in the meta-analysis. We used the fixed effects model to analyze data and I2 and p values to indicate heterogeneity. Results show that FA treatment can effectively improve rodents’ spatial memory ability in MWM and Y maze experiments (I2 ≥ 70, p < 0.005), and reduce the deposition of Aβ in the brains of various model animals (I2 ≥ 50, p < 0.005). The potential mechanisms include anti-amyloidogenesis, anti-inflammation, anti-oxidation, mitochondrial protection, and inhibition of apoptosis. In conclusion, we systematically review and meta-analyze the literature reporting the effects of FA treatment on AD rodent models and solidify the benefits of FA in reducing Aβ deposition and improving memory in preclinical experiments. We also point out the limitations in the current research design and provide a strategy for the production research of FA in the future.

Autophagy is a conserved bulk degradation and recycling process that plays important roles in multiple biological functions, including inflammatory responses. As an important component of the innate immune system, macrophages are involved in defending cells from invading pathogens, clearing cellular debris, and regulating inflammatory responses. During the past two decades, accumulated evidence has revealed the intrinsic connection between autophagy and macrophage function. This review focuses on the role of autophagy, both as nonselective and selective forms, in the regulation of the inflammatory and phagocytotic functions of macrophages. Specifically, the roles of autophagy in pattern recognition, cytokine release, inflammasome activation, macrophage polarization, LC3-associated phagocytosis, and xenophagy are comprehensively reviewed. The roles of autophagy receptors in the macrophage function regulation are also summarized. Finally, the obstacles and remaining questions regarding the molecular regulation mechanisms, disease association, and therapeutic applications are discussed.

Nitric oxide (NO) is an important mediator of inflammation response and the production of NO has been linked to a variety of diseases, including tumors, inflammation and central nervous system diseases. In macrophages, a high level of NO is generated by iNOS during inflammatory responses triggered by cytokines or pathogens. Autophagy, a cellular bulk degradation process via lysosome, has been implicated in many disease conditions including inflammation. In this study, we have reported the previously unknown role of autophagy in regulating iNOS levels in macrophages, both under basal and Lipopolysaccharides (LPS)-induced conditions. Our data showed that iNOS levels accumulated upon autophagy inhibition and decreased upon autophagy induction. iNOS interacted and co-localized with autophagy receptor p62/SQSTM1, especially under LPS-stimulated condition in macrophages. Moreover, the immunostaining data revealed that iNOS also co-localizes with the autophagosome marker LC3 and lysosome marker LAMP1, especially under lysosomal inhibition conditions, indicating iNOS is an autophagy substrate. Finally, we showed that autophagy negatively regulated the generation of NO in macrophages, which is consistent with the changes of iNOS levels. Collectively, our study revealed a previously unknown mechanism by which autophagy regulates iNOS levels to modulate NO production during inflammation.