Stress hormones hasten Alzheimer's onset, progression

Research suggests stress hormones play a central role in the development and progression of Alzheimer's

Stress hormones appear to rapidly exacerbate the formation of brain lesions that are the hallmarks of Alzheimer's disease, according to researchers at UC Irvine. The findings suggest that managing stress and reducing certain medications prescribed for the elderly could slow down the progression of this devastating disease.

Frank LaFerlaPhoto: UC Irvine

In a study with genetically modified mice, Frank LaFerla, professor of neurobiology and behavior, and a team of UCI researchers found that when young animals were injected for just seven days with dexamethasone, a glucocorticoid similar to the body's stress hormones, the levels of the protein beta-amyloid in the brain increased by 60 percent. When beta-amyloid production increases and these protein fragments aggregate, they form plaques, one of the two hallmark brain lesions of Alzheimer's disease. The scientists also found that the levels of another protein, tau, also increased. Tau accumulation eventually leads to the formation of tangles, the other signature lesion of Alzheimer's. The findings appear in this week's issue of the Journal of Neuroscience.

"It is remarkable that these stress hormones can have such a significant effect in such a short period of time," LaFerla said. "Although we have known for some time that higher levels of stress hormones are seen in individuals in the early stages of Alzheimer's, this is the first time we have seen how these hormones play such a direct role in exacerbating the underlying pathology of the disease."

The researchers injected four-month-old transgenic mice with levels of dexamethasone similar to the level of hormones that would be seen in humans under stress. At this young age, there would be little formation of plaques and tangles in the brains of the mice. After one week, the scientists found that the level of beta-amyloid in the brains of the animals compared to what is seen in the brains of untreated eight- to nine-month-old mice, demonstrating the profound consequence of glucocorticoid exposure. When dexamethasone was given to 13-month-old mice that already had some plaque and tangle pathology, the hormone again significantly worsened the plaque lesions in the brain and led to increased accumulation of the tau protein.

"Although we expected that this drug, which, like the stress hormone cortisol, activates glucocorticoid receptors, might have some effect on plaques and tangles, it was surprising to find that such large increases were induced in relatively young mice," said James L. McGaugh, research professor of neurobiology and behavior and co-author of the paper.

The increased accumulation of beta-amyloid and tau appears to work in a "feedback loop" to hasten the progression of Alzheimer's. The researchers found that the higher levels of beta-amyloid and tau led to an increase in the levels of the stress hormones, which would come back to the brain and speed up the formation of more plaques and tangles.

According to the researchers, these findings have profound implications for how to treat the elderly who suffer from Alzheimer's disease.

"This study suggests that not only is stress management an important factor in treating Alzheimer's disease, but that physicians should pay close attention to the pharmaceutical products they prescribe for their elderly patients," said Kim Green, a postdoctoral researcher in neurobiology and behavior and first author of the paper. "Some medications prescribed for the elderly for various conditions contain glucocorticoids. These drugs may be leading to accelerated cognitive decline in patients in the early stages of Alzheimer's."

Alzheimer's disease is a progressive neurodegenerative disorder that affects 4.5 million to 5 million adults in the United States. If no effective therapies are developed, it is estimated that 13 million Americans will be afflicted with the disease by 2050.

In recent years, LaFerla has been at the forefront of Alzheimer's research. He and other members of his research team developed the transgenic mice used in this study, which are now a model for studying Alzheimer's around the world. Earlier this year, he announced work on a new compound that not only relieves the cognitive symptoms of Alzheimer's disease, but also reduces the plaques and tangles in the brain.

Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM.
Glucocorticoids Increase Amyloid- and Tau Pathology in a Mouse Model of Alzheimer’s Disease
J. Neurosci. 2006 26: 9047-9056.   [Abstract]