Stress exacerbates many, if not most, diseases. That stress appears to play a role in Alzheimer disease progression is not surprising; however, a molecular mechanism underlying this phenomenon has been lacking. In this paper, Rissman et al. demonstrate a pathway whereby an "emotional" stressor, such as restraint stress, can alter tau phosphorylation in mice. This effect is independent of glucocorticoids, but dependent on corticotropin releasing factor (CRF) receptors.

Our group recently published a very similar study, assessing the effect of several stressors, including restraint stress, on interstitial fluid (ISF) Aβ levels (Kang et al., 2007). We demonstrated that restraint stress acutely increased ISF Aβ levels, which was dependent on CRF but independent of glucocorticoids. Using very different approaches, our group and Rissman and colleagues may have identified the same pathway, one which could contribute to the two major Alzheimer disease pathologies. In the future, hopefully we will determine if the mechanisms from both of...  Read more

Stress exacerbates many, if not most, diseases. That stress appears to play a role in Alzheimer disease progression is not surprising; however, a molecular mechanism underlying this phenomenon has been lacking. In this paper, Rissman et al. demonstrate a pathway whereby an "emotional" stressor, such as restraint stress, can alter tau phosphorylation in mice. This effect is independent of glucocorticoids, but dependent on corticotropin releasing factor (CRF) receptors.

Our group recently published a very similar study, assessing the effect of several stressors, including restraint stress, on interstitial fluid (ISF) Aβ levels (Kang et al., 2007). We demonstrated that restraint stress acutely increased ISF Aβ levels, which was dependent on CRF but independent of glucocorticoids. Using very different approaches, our group and Rissman and colleagues may have identified the same pathway, one which could contribute to the two major Alzheimer disease pathologies. In the future, hopefully we will determine if the mechanisms from both of these studies do indeed overlap, and if so, how they are linked. And, of course most importantly, if this pathway does contribute to AD progression, we would like to determine if we can modulate the pathway to alleviate disease.

View all comments by John Cirrito

Sawchenko reports that tau phosphorylation is abrogated in the absence of CRFR1. Bale and colleagues report reduced ACTH in CRFR1-deficient mice; therefore, I find it interesting that Nasman and colleagues report a blunted ACTH response to CRF in AD (1,2). I had expected already reduced CRFR1 expression in AD. I have proposed that reduced expression of ACTH due to chronic hypercortisolism in AD may result in the reported reduced levels of the ACTH responsive, seladin-1 (3). A new study by Lamsa and colleagues report that there may be an association with DHCR24 which encodes seladin-1 and AD (4). It will be interesting to see the ACTH levels following antalarmin treatment in AD and furthermore, whether seladin-1 is affected.

References:
1. Bale TL, Picetti R, Contarino A, Koob GF, Vale WW, Lee KF. Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. J Neurosci. 2002 Jan 1;22(1):193-9. Abstract

2. See comment by Mary Reid

3. Näsman B, Olsson T, Fagerlund M, Eriksson S, Viitanen M, Carlström K. Blunted adrenocorticotropin and increased adrenal steroid response to human corticotropin-releasing hormone in Alzheimer's disease. Biol Psychiatry. 1996 Mar 1;39(5):311-8. Comment in: Biol Psychiatry. 1998 Sep 1;44(5):374-6. Abstract

4. Lämsä R, Helisalmi S, Hiltunen M, Herukka SK, Tapiola T, Pirttilä T, Vepsäläinen S, Soininen H. The association study between DHCR24 polymorphisms and Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet. 2007 May 17; [Epub ahead of print] Abstract

View all comments by Mary Reid