Stress And The Development Of Alzheimer Tangles

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Alzheimer's disease is defined by the accumulation of amyloid plaques and neurofibrillary tangles. While plaques accumulate outside of brain cells, tangles litter the inside of neurons. They consist of a modified form of the tau protein, which - in its unmodified form - helps to stabilize the intracellular network of microtubules. In Alzheimer's disease, as well as various other neurodegenerative conditions, phosphate groups are attached to tau. As a result, tau looses its grip on the microtubules, and starts to collapse into insoluble protein fibers, which ultimately cause cell death.

Previous studies had shown that extreme physiological stress, such as plunging mice into ice water or starving them for three days, can induce tau phosphorylation. "But what we wanted to know was whether exposure to milder stress, of the kind we experience in our daily lives, can induce tau phosphorylation," explains senior research associate and first author Robert A. Rissman, Ph.D.

Restraining mice for half an hour, a situation that replicates the body's reaction to low-level anxiety, fear or social stress, resulted only in a transient phosphorylation of tau. However, when Rissman simulated chronic stress by repeating the procedure every day for two weeks, the modification lasted long enough to let tau molecules tumble off the cytoskeleton and pile up in insoluble heaps of protein. The first thing you consider when you think about stress-induced changes in the brain is glucocorticoids because they are such pervasive mediators of stress responses, says Rissman. But even without available glucocorticoids, tau was still modified under stressful conditions and he had to look elsewhere. "The next obvious candidate was the CRF system, which has been broadly implicated in many kinds of stress adaptation," he says.

"A long-term study of about 800 members of religious orders had found that the people who were most prone to stress were twice as likely to develop Alzheimer's disease, but the nature of the link between the two has been elusive," says Paul E. Sawchenko, Ph.D., a professor in the Neuronal Structure and Function Laboratory, who led a phalanx of Salk researchers contributing to the current study. The group's findings, detailed in the Journal of Neuroscience, suggest that the brain-damaging effects of negative emotions are relayed through the two known corticotropin-releasing factor receptors, CRFR1 and CRFR2, which are part of a central switchboard that mediates the body's responses to stress and stress-related disorders.