Alzheimer's disease (AD) is a multi-factor neurodegenerative disease characterized by the deposition of amyloid plaques in the brain and the presence of neurofibrillary tangles in neurons (Calsolaro and Edison, 2016a). The elderly populations are the most commonly affected people by AD. Currently, there is no definitive effective biomedical remedy available (Graff-Radford et al., 2021). The main treatments of AD are to relieve symptoms and to delay the disease progression. Controversy has arisen due to the adverse reactions observed in clinical trials of FDA-approved drugs for AD, including aducanumab and lecanemab (Ferrari and Sorbi, 2021). Therefore, it is imperative to discover a medication for addressing AD with minimum adverse reactions.

Research has indicated that neuroinflammation is a crucial factor in the development of neurodegenerative disorders such as AD, Huntington's disease, and Parkinson's disease (Heneka et al., 2015; Spangenberg and Green, 2017). Neuroinflammation that occurs in the brain as a result of the activations of both microglia and astrocytes could lead to an immune response. Microglia, the macrophages that reside in the central nervous system (CNS), play a crucial role in the growth and repair of neurons (Calsolaro and Edison, 2016b). Several studies have indicated the presence of cortical microglia alongside the amyloid accumulation in patients of AD, while the brains of AD patients also exhibit activated microglia and reactive astrocytes (Sarlus and Heneka, 2017). The regulation of pro-inflammatory factors (e.g., NO, TNF-α, IL-6, COX-2, and INOS) and anti-inflammatory factors such as IL-4 enables microglia to exert control over immune metabolism within the brain. To date, significant advancements have been achieved in the investigations of AD, focusing on the targeting of microglia as a potential treatment for AD at its initial stages (Fricker et al., 2018).

Autophagy could fulfill the metabolic requirements of the cells and the regeneration of organelles (Dhapola et al., 2021; Di Meco, Curtis, Lauretti and Pratico, 2020). Furthermore, autophagy has the ability to safeguard cells against lack of nutrients and react to cytotoxicity. Autophagy is well-known as a basic defense mechanism that has the ability to trigger an independent inflammatory reaction within cells, while the suppression of autophagy decelerates the initiation of neuroinflammatory reactions while enhancing the preservation of neuroinflammatory responses. Recent studies revealed undeveloped autophagosome clusters and deceased neurons in the brains of patients with AD (Hou et al., 2019). In AD models, two widely used autophagy agonists, i.e., rapamycin and Earle's Balanced Salt Solution (EBSS), are revealed with the ability to enhance the breakdown of Aβ plaques, ameliorate cognitive impairment, and safeguard neurons against harms (Eshraghi et al., 2022). Therefore, autophagy plays a crucial role in the initial control of AD.

The 4-octyl itaconate (4-OI; PubChem CID 14239884) has been revealed with the ability to permeate cells. 4-OI has the ability to control the activation of macrophages and the inflammatory response as well as to decrease the production of reactive oxygen species (ROS) and the release of factors that promote inflammation (Liao et al., 2019a; Mills et al., 2018a). Currently, the impact of 4-OI on AD is still unclear, particularly its influence on neuroinflammation and autophagy. The goals of our study were to explore the response 4-OI to AD and the molecular mechanism underlying the therapeutic effects of 4-OI on the treatment and prevention of AD.