Stress proteins and regulation of microglial amyloid-β phagocytosis

Abstract

Recent studies have indicated that prolonged dysfunction and/or stress in the endoplasmic reticulum (ER) may contribute to pathogenesis and neurodegeneration. The disorder caused by misfolding and aggregation of proteins has been referred to as conformational disease, including Alzheimer's disease (AD). AD is characterized by the accumulation of extracellular amyloid-β1-42 (Aβ42) fibrils with reactive microglia. Understanding the balance of production and clearance of Aβ42 is the key to elucidating amyloid plaque homeostasis. We have recently found that microglial phagocytosis of Aβ42 may be essentially driven by dynamic reorganization of the actin cytoskeleton through the pathway of WAVE and Rac1. In addition, an extracellular stress protein, such as Hsp90, enhances Aβ 42 phagocytosis. HMGB1 inhibits microglial phagocytosis of Aβ42, and it binds Aβ42 and stabilizes the oligomerization. These results suggest that microglial clearance of Aβ42 may be another option for investigations in the search for a therapeutic strategy for AD, in addition to the study of production and degradation of Aβ42.