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PHOSPHATASE ACTIVITY DURING SLEEP/WAKE CYCLES REGULATES APP PROCESSING AND BRAIN ISF AMYLOID-BETA LEVELS
Abstract
Aims
Evidence in both APP transgenic animal models and in humans demonstrate that brain Abeta levels fluctuate with the diurnal cycle; Abeta within the brain extracellular fluids are high during wakefulness and low during sleep. In mice and in humans, sleep deprivation increases Abeta levels acutely. Chronic alterations in sleep have a similar impact on amyloid plaque accumulation in these mice. We hypothesized that sleep is altering an intracellular signaling pathway that ultimately regulates Abeta generation and secretion into the brain ISF.
Methods
We used in vivo microdialysis to measure brain ISF Abeta levels every hour over several days in living APP transgenic mice while manipulating orexin receptor signaling and downstream intracellular signaling pathways, such as the extracellular regulated kinase (ERK) and phosphatases such as SHP2 and PP2A.
Results
Similar to previous studies, we detected a diurnal fluctuation in ISF Abeta levels during the sleep/wake cycle. Inhibiting Extracellular Regulated Kinase (ERK), increased ISF Abeta levels by 50% and blocked the fluctuation in ISF Abeta, suggesting that ERK plays a role in the diurnal rhythm of Abeta. SHP-2 is a phosphatase that dephosphorylates phospho-ERK to deactivate it. Inhibition of SHP-2 reduces ISF Abeta levels and also blocks the diurnal fluctuation.
Conclusions
Our data suggest that there is an inverse relationship between the amount of phospho-ERK and the activity of SHP-2 which determines how much Abeta is produced in response to the physiological fluctuation in sleep/wake.