Amyloid-beta regulation in the brain interstitial fluid of a mouse model of Alzheimer's disease

The extracellular aggregation of the amyloid-beta (Abeta) peptide in the brain is a critical event in the pathogenesis of Alzheimer's disease (AD). Abeta peptides are produced by neurons and released into the brain interstitial fluid (ISF). The aggregation of Abeta into toxic species within the brain extracellular space is believed to be concentration-dependent. Therefore, identifying mechanisms that regulate AP levels within the ISF may provide important insights into AD pathogenesis and potential therapeutics. Synaptic activity has been shown to regulate Abeta release from neurons; however, little is known about how extracellular Abeta levels are regulated by environment or physiological stimuli. In this study, we investigated how Abeta is regulated by environment or normal, physiological events. We found that behavioral stressors can increase ISF Abeta levels in human amyloid precursor protein transgenic mice. Isolation stress over 3 months increased Abeta levels by 84%. Similarly, acute restraint stress increased Abeta levels over hours. We wanted to determine the underlying mechanism of Abeta regulation by stress and used acute stress paradigm as a tool. We discovered that the effects of acute restraint stress were mediated by corticotropin releasing factor (CRF), but not corticosterone. Neuronal activity was also required for the effects of acute restraint stress. These results suggest a mechanism by which behavioral stress may affect AD pathogenesis. We also investigated the endogenous regulation of ISF Abeta during normal sleep-wake behavior. We found that brain ISF levels of Abeta fluctuate dynamically with the sleep-wake cycle. Abeta levels correlate strongly with wakefulness. We wanted to examine whether sleep regulates Abeta levels. Drugs or treatments that alter the amount of time awake or asleep, including orexin, affect Abeta levels in a manner consistent with their effects on the sleepwake cycle and synaptic activity, suggesting that sleep may regulate Abeta levels. This finding suggests that understanding the effect of sleep on Abeta metabolism may provide new insights into AD pathogenesis and potentially treatment.