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

Aggregation of the amyloid-β (Aβ) peptide in the extracellular space of the brain is critical in the pathogenesis of Alzheimer's disease. Aβ 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 Aβ levels, we assessed the effects of chronic and acute stress paradigms in amyloid precursor protein transgenic mice. Isolation stress over 3 months increased Aβ levels by 84%. Similarly, acute restraint stress increased Aβ 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 Aβ. Thus, behavioral stressors can rapidly increase ISF Aβ through neuronal activity in a CRF-dependent manner, and the results suggest a mechanism by which behavioral stress may affect Alzheimer's disease pathogenesis.