Chronic Treatment with Aβ42 with a Toxic Conformer and LPS Induces Inflammatory Responses in BV-2 Microglia with Dysregulation of Hypoxia-Inducible Factor Expression

Amyloid beta (A beta) plays a key role in the pathology of Alzheimer's disease (AD) and is toxic owing to its ability to aggregate into oligomers and fibrils. A beta has high aggregative ability and potent toxicity due to the toxic turn at positions 22 and 23. Furthermore, APP knock-in mice producing E22P-A beta with the toxic turn exhibited AD-related phenotypes such as cognitive impairment, A beta plaque accumulation, and tau hyperphosphorylation. In these mice, it is suggested that the activation of neuroinflammation and dysregulation of hypoxia-inducible factor (HIF) expression in the hippocampus contribute to the pathogenesis of AD-related phenotype. However, it remains unclear which cells are responsible for the dysregulation of HIF expression and the neuroinflammation which was induced by E22P-A beta with the toxic turn. Here, we investigated the effects of chronic treatment with E22P-A beta 42 and lipopolysaccharides (LPS) on the inflammatory response in BV-2 microglia. Chronic treatment with E22P-A beta 42 and LPS increased nitric oxide production and the expression of interleukin- 6 ( IL-6), whereas it reduced the expression of HIF-1 alpha and HIF-3 alpha in BV-2 microglia. The reduction of HIF-1 alpha caused by E22P-A beta 42 and LPS was milder than that caused by LPS. Furthermore, chronic treatment with E22P-A beta 42 and LPS increased the nuclear translocation of nuclear factor-kappaB (NF-.B). E22P-A beta 42 could enhance the inflammatory response of microglia with abnormal HIF signaling and contribute to the progression of AD pathology.

Automated summary

Chronic treatment with E22P-A beta 42 and LPS was found to increase nitric oxide production and interleukin-6 (IL-6) expression, while reducing the expression of HIF-1 alpha and HIF-3 alpha in BV-2 microglia. Furthermore, it was observed that E22P-A beta 42 and LPS enhanced nuclear translocation of nuclear factor-kappaB (NF-.B). These findings suggest that E22P-A beta 42 may enhance the inflammatory response of microglia through abnormal HIF signaling, contributing to the progression of Alzheimer's disease pathology.