Stress and AD: How the Brain Responds Makes All the Difference (Part 3)

Scientists believe that stress has a hand in Alzheimer’s disease, and that stress hormones can nudge along the disease’s pathology. However, many questions remain unanswered. For example, what is it about stress and glucocorticoids that relates to normal aging? Some animal studies suggest that circulating glucocorticoid levels go up with age (see, e.g., Sapolsky et al., 1986), but others don’t (see Sonntag et al., 1987). The classic glucocorticoid hypothesis of brain aging proposes that too much stress “ages” the brain. As an oft-quoted line from Hans Selye, the pioneering endocrinologist known as the “Father of Stress,” goes: “Every stress leaves an indelible scar, and the organism pays for its survival after a stressful situation by becoming a little older.”

In reality, the picture has been complicated considerably since Selye’s days, Philip Landfield told Alzforum. Landfield, who is at the University of Kentucky, Lexington, ran microarray analyses using a panel of hippocampal genes on brain extracts from aged animals and those with high plasma corticosterone levels. He found that aging and elevated corticosterone shifted gene expression in opposite directions for the most part, rather than in the same direction, as predicted by the glucocorticoid aging hypothesis (see Landfield et al., 2007). Expression changes were also cell type-specific. It appears that aging magnifies the effects of glucocorticoids on some processes, for example, catabolism in neurons, while weakening their effects on other processes, such as inflammation in astrocytes, Landfield said. This latter finding fits with the observation that neuroinflammation increases with age, even in the presence of high levels of glucocorticoids that normally dampen inflammation. Landfield proposes that, rather than glucocorticoids “aging” the brain, the aging process instead changes the way glucocorticoids act in the brain.

Other researchers agree that the brain’s response to stress may be the crucial factor. “We know that as people get older, the ability to turn off the endocrine response to stress gets slightly worse in general. The homeostatic mechanism is getting lost,” said Osborne Almeida, Max Planck Institute of Psychiatry, Munich, Germany. He also noted that epigenetic changes in DNA, which often occur during early development, may play a role in an individual’s response to stress. “Early life stress, for example, can have enormous repercussions for you throughout life,” he said.

The idea that the brain’s response is the key variable highlights the importance of receptors and specific signaling pathways. For example, a genetic variant of the glucocorticoid receptor (GR) lowers dementia risk (see Part 1). The downstream effectors of GRs are also very important. “Glucocorticoids work in large part by regulating other genes, and so [we need] to understand what those other genes are and how they build into a picture, a network that underpins both cognition and maybe pathogenesis,” said Jonathan Seckl at the University of Edinburgh, U.K.

Work by Mark Mattson at the National Institute on Aging in Baltimore, Maryland, among others, has shown that caloric restriction, which extends lifespan and improves cognition, shoots up levels of circulating glucocorticoids (see also ARF related news story). This contradicts the idea that higher glucocorticoid levels always harm memory (see, e.g., Brown, 2009). What explains this seeming paradox? “What we think is happening is that the neurons respond to glucocorticoids differently,” Mattson told ARF. “With dietary calorie restriction, the expression of glucocorticoid receptors (GRs) in hippocampal neurons decreases.” (See Lee et al., 2000.) With chronic uncontrollable stress, by contrast, levels of the “good” mineralocorticoid receptor (MR) receptor go down instead. Mattson noted that GR activation suppresses brain-derived neurotrophic factor (BDNF) production, while MR activation does not. BDNF plays crucial roles in learning, memory, and brain health. “The bottom line is, we think the signaling pathways by which neurons respond to glucocorticoids are very important in determining whether glucocorticoids have a good or bad effect on the neuron,” Mattson said.

Several recent studies implicate glucocorticoids in memory impairment via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme converts inactive glucocorticoid metabolites to active forms in the brain, and so amplifies the effects of these hormones. Seckl and colleagues report that 11β-HSD1 is up in the brain of aged mice, and that inhibiting this enzyme improves memory. Overexpressing it, meanwhile, brings on premature memory problems (see Holmes et al., 2010 and Sooy et al., 2010). Seckl said that the high levels of glucocorticoids found in elderly wild-type mice saturate the high-affinity MRs and spill over onto the low-affinity GRs, so lowering glucocorticoid levels by knocking out 11β-HSD1 helps neurons make the switch from GR to MR. Joyce Yau, working in Seckl’s lab, used glucocorticoid receptor blockers in aged control and 11β-HSD1 knockout mice to investigate the roles of the GR and MR receptors in memory (see Yau et al., 2011). In the aged knockout mice, which are cognitively sharp, GR blockers had no effect, but MR blockers worsened memory. Conversely, in the elderly control mice, which have poor memory, MR blockers had no effect, and GR blockers sharpened memory. The results support the idea that when glucocorticoids act through GR receptors, they harm memory, but when they act through MR receptors, they enhance it. Similarly, researchers led by Lynne Rueter at Abbott Laboratories, Abbott Park, Illinois, report that 11β-HSD1 inhibitors can improve memory in wild-type rats (see Mohler et al., 2011). Rueter declined to speak with Alzforum for more information on these inhibitors.

In the October 5 Journal of Neuroscience, researchers led by Steven Thomas at the University of Pennsylvania, Philadelphia, describe a mechanism by which acute stress impairs memory retrieval (a well-known effect of glucocorticoids). First author Keith Schutsky found that during acute stress, glucocorticoids and norepinephrine both act through the β2-adrenergic receptor to scramble memory. Activation of this receptor reduces cAMP signaling, known to be important for memory. Conversely, norepinephrine acting on the β1-adrenergic receptor increases cAMP and facilitates memory retrieval. Norepinephrine and glucocorticoids may therefore have a synergistic harmful effect in acute stress that is mediated by the β2 receptor, Thomas suggested. Identifying a particular receptor opens up possibilities for intervening in harmful pathways while sparing positive effects.

With specific enzymes and receptors being implicated in memory suppression, are any of them suitable targets for therapeutic trials? Several experts told ARF that they first need to understand more about the basic science and mechanisms behind stress. The stress system is enormously complicated, and perturbing it could do more harm than good. For example, the synthetic glucocorticoid prednisone worsened some behavioral symptoms when given to AD patients as an anti-inflammatory (see Aisen et al., 2000). In addition, Thomas noted that different types of stress may require distinct therapeutic approaches. One non-pharmacological way to lower stress is through relaxation techniques such as yoga and meditation, but very few studies have looked at the effects of these interventions on cognition and brain health (see Pagnoni and Cekic, 2007; Doraiswamy and Xiong, 2007).

Currently, some of the most promising therapeutic approaches include 11β-HSD1 inhibitors and CRF receptor antagonists. A small study by Seckl’s group found that 11β-HSD1 inhibition improves cognition in elderly diabetic men (see Sandeep et al., 2004). Rueter at Abbott Laboratories is doing preclinical work on such inhibitors, and Merck is also in the hunt (see ARF related news story), but neither of them has listed any current dementia trials targeting this enzyme. Seckl noted, however, that 11β-HSD1 inhibitors have been “modestly successful” for several companies in metabolic disease and diabetes trials, and he predicted dementia trials might be next.

CRF receptor antagonists are similarly on the verge, with no dementia trials currently listed. However, several companies, such as Eli Lilly, Bristol-Myers Squibb Company, and SmithKline Beecham Limited, have filed patents for CRF1 antagonists in the last year or so, suggesting that preclinical work is ongoing. The patents cover conditions ranging from depression, anxiety, and irritable bowel syndrome to neurodegenerative conditions.

Other potential treatments also target receptors. Kim Green at the University of California, Irvine, points out that the glucocorticoid receptor antagonist tau mutant mice mifepristone (RU-486) may be a promising treatment for AD (see also Dhikav and Anand, 2007). Green sees encouraging results in AD animal models with mifepristone (paper submitted). The drug is currently in several clinical trials for conditions such as depression, post-traumatic stress disorder, and metabolic syndrome. A small AD trial in 2002 reportedly showed cognitive improvement (see Pomara et al., 2002; Pomara et al., 2006).

It seems clear that the study of stress and AD is still in its infancy, Landfield told ARF. “One thing we’ve learned, especially since we began working with microarray analyses, is that everything is enormously more complicated than we thought. I do think a major key to unhealthy brain aging and neurodegeneration may lie in the role of glucocorticoids in the brain, but it’s not going to be a simple puzzle. We’re going to need a Rosetta stone of some sort.”—Madolyn Bowman Rogers.

References:
Schutsky K, Ouyang M, Castelino CB, Zhang L, Thomas SA. Stress and glucocorticoids impair memory retrieval via {β}2-adrenergic, Gi/o-coupled suppression of cAMP signaling. J Neurosci. 2011 Oct 5;31(40):14172-81. Abstract

Yau JL, Noble J, Seckl JR. 11β-hydroxysteroid dehydrogenase type 1 deficiency prevents memory deficits with aging by switching from glucocorticoid receptor to mineralocorticoid receptor-mediated cognitive control. J Neurosci. 2011 Mar 16;31(11):4188-93. Abstract

This is Part 3 of a three-part series. See Part 1 http://wp.me/p1FBFj-3OZ. See Part 2 http://wp.me/p1FBFj-3P3

Download a PDF of the entire series.

Citation