Orexin Impairs the Phagocytosis and Degradation of Amyloid-ß Fibrils by Microglial Cells.

ABSTRACT

BACKGROUND: Intracranial accumulation of amyloid-ß (Aß) is a characteristic finding of Alzheimer's disease (AD). It is thought to be the result of Aß overproduction by neurons and impaired clearance by several systems, including degradation by microglia. Sleep disturbance is now considered a risk factor for AD, but studies focusing on how sleep modulates microglial handling of Aß have been scarce. OBJECTIVE: To determine whether phagocytosis and degradation of extracellular Aß fibrils by BV2 microglial cells were impaired by treatment with orexin-A/B, a major modulator of the sleep-wake cycle, which may mimic sleep deprivation conditions. METHODS: BV2 cells were treated with orexin and Aß for various durations and phagocytic and autophagic processes for degradation of extracellular Aß were examined. RESULTS: After treatment with orexin, the formation of actin filaments around Aß fibrils, which is needed for phagocytosis, was impaired, and phagocytosis regulating molecules such as PI3K, Akt, and p38-MAPK were downregulated in BV2 cells. Orexin also suppressed autophagic flux, through disruption of the autophagosome-lysosome fusion process, resulting in impaired Aß degradation in BV2 cells. CONCLUSIONS: Our results demonstrate that orexin can hinder clearance of Aß through the suppression of phagocytosis and autophagic flux in microglia. This is a novel mechanism linking AD and sleep, and suggests that attenuated microglial function, due to sleep deprivation, may increase Aß accumulation in the brain.