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

doi:10.1073/pnas.0700148104

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

Departments of *Neurology,
^†Psychiatry,
^‡Anatomy and Neurobiology, and
^§Molecular Biology and Pharmacology,
^¶Hope Center for Neurological Disorders, and
^‖Alzheimer's Disease Research Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110

Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved May 8, 2007 (received for review January 7, 2007)

Abstract

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.

Footnotes

**To whom correspondence should be addressed. E-mail: holtzman{at}neuro.wustl.edu
Author contributions: J.-E.K., J.R.C., H.D., J.G.C., and D.M.H. designed research; J.-E.K. and H.D. performed research; J.-E.K., J.R.C., and D.M.H. analyzed data; and J.-E.K., J.R.C., J.G.C., and D.M.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Abbreviations:

Aβ,

amyloid-β;

αCRF9–41,

antagonist of CRF receptors;

aCSF,

artificial cerebrospinal fluid;

AD,

Alzheimer's disease;

APP,

amyloid precursor protein;

CRF,

corticotropin-releasing factor;

CTF,

C-terminal fragment;

h/r CRF,

human/rat CRF;

ISF,

interstitial fluid;

TTX,

tetrodotoxin.