9 June 2007. It is widely recognized that chronic stress—be it psychological or physical—is bad for one’s health. Yet people may be surprised to hear that it may also predispose to Alzheimer disease. Two papers out this week report how stress alters processing of amyloid-β precursor protein. This story summarizes the findings of David Holtzman and colleagues at Washington University, St. Louis, who have studied the effects of acute and chronic psychological stress in mouse models of AD. An upcoming companion story details work led by Rudy Tanzi and colleagues at Massachusetts General Hospital, Charlestown, who found that physical stress in the form of cerebral ischemia can enhance β-secretase activity. Next week we will cover a third paper slated for publication, which links stress to mild cognitive impairment, often a precursor to AD.

Holtzman and colleagues previously reported that stress impairs learning and memory performance and increases deposition of Aβ in Tg2576 transgenic mice (see Dong et al., 2004). Why stress exacerbated Aβ pathology was a puzzle. In this week’s PNAS online, first author Jae-Eun Kang and colleagues report that both acute and chronic stress appear to increase production of Aβ, and that this may result from elevated neuronal activity.

Kang and colleagues used microdialysis to measure interstitial fluid (ISF) Aβ in the brains of transgenic mice that were either housed for long periods in relative isolation or acutely stressed by physical restraint. Both stressors led to significant increases in Aβ. After 3 months of isolation, ISF Aβ concentration was 85 percent higher than in controls. In the acute test, 3 hours of restraint were enough to bump up levels by about 20 percent in as little as an hour, with Aβ peaking at 32 percent higher than normal about 13 hours after the test began. In the case of chronic stress, analysis of whole hippocampus extracts by ELISA showed that soluble Aβ40 and Aβ42 concentrations were both increased (by 38 and 59 percent, respectively), though the Aβ40/42 ratio remained unchanged. Not surprisingly, since the researchers used young animals for this test, they detected no plaques. Nevertheless, the authors conclude that an increase in ISF Aβ probably accelerates deposition of the peptide seen in older stressed mice.

Is the Aβ increase due to greater production or poorer clearance? Holtzman and colleagues favor the former. In the stressed animals, Kang and colleagues detected no changes in levels of insulin-degrading enzyme or neprilysin, two enzymes that degrade Aβ. This does not preclude enhanced degradation by other enzymes or more rapid clearance of whole peptide. However, the authors found that tetrodotoxin, a potent inhibitor of neural activity, blocked the restraint-induced Aβ increase. This fits with the idea that Aβ release is coupled to neural activity, and that heightened neural activity in response to stress drives production of more Aβ.

What might drive the increases in neural activity? The researchers initially examined glucocorticoid hormones, which mediate stress responses, but failed to detect a spike in ISF Aβ after administering acute corticosterone to the mice. Next, they turned to what happens upstream of glucocorticoid release. Release is governed by corticotrophin-releasing factor (CRF), best known for being produced in the hypothalamus and stimulating the pituitary to release adrenocorticotropic hormone. But CRF is also made locally in the brain in response to stress, and it can bind to specific CRF receptors and stimulate excitatory neurotransmission (see review by Baram and Hatalski, 1998). It appears as if locally produced CRF mediates the effects of stress on Aβ, at least for chronic stress. That’s because infusing CRF into the brain elevated ISF Aβ in a dose-dependent manner. Furthermore, acute stress elevated CRF, while infusion of a CRF inhibitor prevented the restraint-induced elevation in Aβ. By contrast, in the case of chronic stress, the researchers find no increase in ISF CRF, suggesting that another mechanism may be at play.

How these findings relate to human stress remains to be seen. However, it is established that repeated acute physical stress, such as head trauma, can lead to AD-like pathology, including deposition of Aβ (see ARF related news story). “The relationship among stress, CRF, and ISF Aβ levels suggests that CRF may play a role in AD pathogenesis and that CRF and CRF signaling pathways are therapeutic targets to modulate processes that affect Aβ metabolism,” conclude the authors. Regular doses of rest and relaxation may not go amiss, either.—Tom Fagan.

Reference:
Kang J-E, Cirrito JR, Dong H, Csernansky JG, Holtzman DM. Acute stress increases interstitial fluid amyloid-beta via corticotrophin-releasing factor and neuronal activity. PNAS. 2007, June 4. Early online edition. Abstract