Acute stress increases interstitial fluid amyloid-β via corticotropin-releasing factor and neuronal activity

Aggregation of the amyloid-beta (A beta) peptide in the extracellular space of the brain is critical in the pathogenesis of Alzheimer's disease. A beta is produced by neurons and released into the brain interstitial fluid (ISF), a process regulated by synaptic activity. To determine whether behavioral stressors can regulate ISF A beta levels, we assessed the effects of chronic and acute stress paradigms in amyloid precursor protein transgenic mice. Isolation stress over 3 months increased A beta levels by 84%. Similarly, acute restraint stress increased A beta levels over hours. Exogenous corticotropin-releasing factor (CRF) but not corticosterone mimicked the effects of acute restraint stress. Inhibition of endogenous CRF receptors or neuronal activity blocked the effects of acute stress on A beta. Thus, behavioral stressors can rapidly increase ISF A beta through neuronal activity in a CRF-dependent manner, and the results suggest a mechanism by which behavioral stress may affect Alzheimer's disease pathogenesis.