Circadian Control of Heparan Sulfate Levels Times Phagocytosis of Amyloid Beta Aggregates

Alzheimers Disease (AD) is a neuroinflammatory disease characterized partly by the inability to clear, and subsequent build-up, of amyloid-beta (A{beta}). A{beta} clearance is regulated by several pathways and has a circadian component. However, the mechanism underlying the circadian clearance of A{beta} has not been defined. Myeloid-based phagocytosis, a key mechanism in the metabolism of A{beta}, is circadianly-regulated, presenting a potential mechanism for the circadian clearance of A{beta}. In this work, we revealed that the phagocytosis of A{beta}42 undergoes a daily oscillation that is dependent on the circadian clock. We found the circadian timing of global heparan sulfate proteoglycan (HSPG) biosynthesis was the molecular timer for the clock-controlled phagocytosis of A{beta} and that both HSPG binding and A{beta}42 aggregation were essential for this oscillation. These data highlight that circadian regulation in immune cells may play a role in the intricate relationship between the circadian clock and AD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/442651v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@bca9b3org.highwire.dtl.DTLVardef@29575corg.highwire.dtl.DTLVardef@2673c5org.highwire.dtl.DTLVardef@7a8daa_HPS_FORMAT_FIGEXP M_FIG C_FIG