Alzheimer’s Disease (AD) contributes to most cases of dementia. Its prominent neuropathological features are the extracellular neuritic plaques and intercellular neurofibrillary tangles composed of aggregated β-amyloid (Aβ) and hyperphosphorylated tau protein, respectively. In the past few decades, disease-modifying therapy targeting Aβ has been the focus of AD drug development. Even though it is encouraging that two of these drugs have recently received accelerated US Food and Drug Administration approval for AD treatment, their efficacy or long-term safety is controversial. Tau has received increasing attention as a potential therapeutic target, since evidence indicates that tau pathology is more associated with cognitive dysfunction. Moreover, inflammation, especially neuroinflammation, accompanies AD pathological processes and is also linked to cognitive deficits. Accumulating evidence indicates that inflammation has a complex and tight interplay with tau pathology. Here, we review recent evidence on the interaction between tau pathology, focusing on tau post-translational modification and dissemination, and neuroinflammatory responses, including glial cell activation and inflammatory signaling pathways. Then, we summarize the latest clinical trials targeting tau and neuroinflammation. Sustained and increased inflammatory responses in glial cells and neurons are pivotal cellular drivers and regulators of the exacerbation of tau pathology, which further contributes to its worsening by aggravating inflammatory responses. Unraveling the precise mechanisms underlying the relationship between tau pathology and neuroinflammation will provide new insights into the discovery and clinical translation of therapeutic targets for AD and other tau-related diseases (tauopathies). Targeting multiple pathologies and precision therapy strategies will be the crucial direction for developing drugs for AD and other tauopathies.

Pathological features of Alzheimer’s disease (AD) include aggregation of amyloid beta (Aβ) and tau protein. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been implicated in the toxicity of aggregated Aβ. It remains unclear whether MIF affects hyperphosphorylation and aggregation of tau. The effects of MIF deficiency in tau hyperphosphorylation were examined in Mif −/− mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ) and in APP/PS1 transgenic mice mated with Mif −/− mice. MIF expression and astrocyte activation were evaluated in ICV-STZ mice using immunofluorescence staining. Cultured primary astrocytes were treated with high glucose to mimic STZ function in vitro, and the condition medium (CM) was collected. The level of tau hyperphosphorylation in neurons treated with the astrocyte CM was determined using Western blotting. MIF deficiency attenuated tau hyperphosphorylation in mice. ICV injection of STZ increased astrocyte activation and MIF expression in the hippocampus. MIF deficiency attenuated astrocyte activation in ICV-STZ mice. CM from high glucose-treated WT astrocytes increased tau hyperphosphorylation in cultured primary neurons, an effect absent from Mif −/− astrocytes and WT astrocytes treated with the MIF inhibitor ISO-1. ISO-1 had no direct effect on tau phosphorylation in cultured primary neurons. These results suggest that MIF deficiency is associated with reduced astrocyte activation and tau hyperphosphorylation in the mouse AD models tested. Inhibition of MIF and MIF-induced astrocyte activation may be useful in AD prevention and therapy.

Accumulation of hyperphosphorylated tau is a major neuropathological feature of tauopathies including Alzheimer’s disease (AD). Serum amyloid A (SAA), an acute-phase protein with cytokine-like property, has been implicated in amyloid deposition. It remains unclear whether SAA affects tau hyperphosphorylation. Potential involvement of SAA in tau hyperphosphorylation was examined using intracerebral injection of SAA, and in Saa3 −/− mice receiving systemic administration of lipopolysaccharide (LPS). Induced SAA expression and microglial activation were evaluated in these mice using real-time PCR and/or immunofluorescence staining. Cultured primary neuronal cells were treated with condition media (CM) from SAA-stimulated primary microglial cells. The alteration in tau hyperphosphorylation was determined using Western blotting. Saa3 is the predominant form of SAA proteins induced by LPS in the mouse brain that co-localizes with neurons. Overexpression of SAA by intracerebral injection attenuated tau hyperphosphorylation in the brain. Conversely, Saa3 deficiency enhanced tau phosphorylation induced by systemic LPS administration. Intracerebral injection of SAA also induced the activation of microglia in the brains. IL-10 released to CM from SAA-stimulated microglia attenuated tau hyperphosphorylation in cultured primary neurons. IL-10 neutralizing antibody reversed the effect of SAA in the attenuation of tau phosphorylation. LPS-induced expression of SAA proteins in the brain leads to the activation of microglia and release of IL-10, which in turn suppresses tau hyperphosphorylation in a mouse model of systemic inflammation.

Formyl peptide receptors (FPRs) are G protein-coupled chemoattractant receptors expressed mainly in phagocytic leukocytes. High expression of FPRs has also been detected in several cancers but the functions of FPR1 in tumor invasion and metastasis is poorly understood. In this study, we investigated the expression of FPRs in primary human colorectal cancer (CRC) and analyzed the association of FPRs expression with clinicopathological parameters. The levels of FPRs mRNA, especially those of FPR1, were significantly higher in colorectal tumors than in distant normal tissues and adjacent non-tumor tissues. FPR1 mRNA expression was also associated with tumor serosal infiltration. FPR1 protein expression was both in the colorectal epitheliums and tumor infiltrating neutrophils/macrophages. Furthermore, the functions of FPR1 in tumor invasion and tissue repair were investigated using the CRC cell lines SW480 and HT29. Higher cell surface expression of FPR1 is associated with significantly increased migration in SW480 cells compared with HT29 cells that have less FPR1 membrane expression. Finally, genetic deletion of fpr1 increased the survival rate of the resulting knockout mice compared with wild type littermates in a mouse model of colitis-associated colorectal cancer. Our data demonstrate that FPR1 may play an important role in tumor cell invasion in CRC patients.