Alzheimer disease (AD) is a devastating neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta and formation of intracellular neurofibrillary tangles. Microglia activation and neuroinflammation play important roles in the pathogenesis of AD; Toll-like receptor 4 (TLR4)—a key component of the innate immune system—in microglia is also thought to be involved based on the observed association between TLR gene polymorphisms and AD risk. TLR4 has been shown to exert both detrimental and beneficial effects on AD-related pathologies. In preclinical models, experimental manipulations targeting TLR4 were shown to improve learning and memory, which was related to inhibition of pro-inflammatory cytokine release and reduction of oxidative stress. In this review, we summarize the key evidence supporting TLR4 as a promising therapeutic target in AD treatment.

Many studies have demonstrated that neuroinflammation contributes to the onset and development of Alzheimer’s disease (AD). The infiltration of immune cells in the brain was observed in AD. The purpose of the present study was to verify potential mechanisms and screen out biomarkers related to immune infiltration in AD. We collected the expression profiling datasets of AD patients and healthy donors from the NCBI’s Gene Expression Omnibus (GEO) database. We confirmed that immune-related mechanisms were involved in AD using differentially expressed genes analysis and functional enrichment analysis. We then found that M2 macrophage infiltration was most positively correlated with AD according to the CIBERSORT algorithm and a weighted gene co-expression network analysis (WGCNA). TLR2, FCGR2A, ITGB2, NCKAP1L and CYBA were identified as hub genes correlated with M2 macrophage infiltration in AD. Furthermore, the expression levels of these hub genes were positively correlated with Aβ42 and β-secretase activity. A diagnostic model of these hub genes was constructed, which showed a high area under the curve (AUC) value in both the derivation and validation cohorts. Overall, our work further expanded our understanding of the immunological mechanisms of AD and provided new insights into therapeutic strategies in AD.