Alzheimer's disease: a new suspect

The trigger of Alzheimer's disease may be corticosteroids

LifeSciencesToday based on Newswise: Stress hormone could trigger mechanism for the onset of alzheimersAccording to a study by Temple University scientists, a hormone secreted by the adrenal cortex in response to stress may be a key trigger for the development of late-onset Alzheimer's disease.

Previous studies have shown that in patients with Alzheimer's disease, the level of the hormone glucocorticoid entering the blood in response to stress is two to three times higher than in patients who do not suffer from this neurodegenerative disease.

"Stress is an environmental factor that, apparently, can play a very important role in the development of Alzheimer's disease," says Domenico Pratico, professor of pharmacology and microbiology and immunology at Temple University School of Medicine, who led this study. "If corticosteroid levels are too high for too long, they can damage neurons that are very important for learning and memory and even cause their death."

The researchers conducted a series of experiments to study the mechanisms by which stress leads to the development of brain pathology.

Using triple transgenic mice whose bodies produce proteins associated with the main signs of Alzheimer's disease – beta-amyloid and tau protein - they administered high doses of dexamethasone to one group of animals daily for a week to simulate stress.

While there were no significant differences in the animals' ability to remember at the end of the week, the levels of tau protein in the dexamethasone-treated group were significantly higher. In addition, the animals had either damaged or destroyed synapses that make possible the communication of nerve cells and play a key role in the ability to learn and remember.

"This is surprising, because we have not seen any signs of a significant deterioration in memory, but the pathology that determines the decline in the ability to learn and remember is clearly visible," says Professor Pratiko. "Therefore, we believe we have identified the earliest type of damage preceding memory loss in Alzheimer's disease."

Another surprising result of the study is the absence of the effect of damage to neurons by dexamethasone in the third group of genetically modified mice deprived of the enzyme 5-lipoxygenase.

In previous studies, Professor Pratico and his group have shown that elevated levels of 5-lipoxygenase lead to increased levels of tau protein in areas of the brain that control memory and cognitive abilities, disrupting neural connections and contributing to the development of Alzheimer's disease. In addition, the enzyme 5-lipoxygenase increases the levels of beta-amyloid, which is believed to be the cause of neuronal death and forms beta-amyloid plaques in the brain.

Professor Pratiko considers corticosteroid hormones to be the cause of increased expression and increased levels of 5-lipoxygenase, which in turn increase the levels of tau protein and beta-amyloid.

"What causes the increase in levels of 5-lipoxygenase has long remained unclear, but now we have evidence that it is a stress hormone," he says. "We have identified the mechanism by which a risk factor – high levels of corticosteroids – can lead to the development of the disease. Corticosteroid uses 5-lipoxygenase as a mechanism for synapse damage, which leads to memory impairment and reduced learning ability – two key symptoms of Alzheimer's disease. A reliable proof of this hypothesis is that by blocking 5-lipoxygenase, it is possible to probably prevent the negative effects of corticosteroids."

Article by Joshi et al. Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathology in 3xTg mice is published in the journal Aging Cell.

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