University Of Washington Scientists Look For Cellular Clues To Explain How Estrogen Replacement Therapy May Protect Against Alzheimer's Disease

September 16, 1997

Among its many salutary effects, estrogen seems to protect the brain against the ravages of Alzheimer's disease: numerous clinical studies support that finding. But how does it accomplish this feat? Researchers at the University of Washington in Seattle are involved in a number of basic-science studies that are beginning to provide answers.

Post-menopausal women have somewhat higher rates of Alzheimer's than men. Scientists think the incidence in women is related to the sudden loss of natural estrogen to the brain, as the ovaries cease production during menopause. In men, testosterone converts to estrogen in the brain, where it apparently performs a similar protective function. However, men do not experience the same sudden decrease in hormone levels at midlife.

Estrogen replacement therapy (ERT) restores estrogen levels to those of younger women. Various studies show that ERT protects against Alzheimer's (including the Baltimore Longitudinal Study of Aging, which showed that women on ERT have about half the chance of developing Alzheimer's compared to women not on ERT). But there have not been definitive answers to the question of how estrogen protects neurons (brain cells).

Researchers led by Dr. Daniel Dorsa, UW professor of psychiatry and pharmacology and interim associate dean of medicine for scientific affairs, are examining estrogen's effects at basic cellular levels, studying rat brains and cell cultures.

They are looking for the mechanisms by which estrogen protects against the assaults of Alzheimer's disease, which gradually destroys neurons, leading to dementia and eventual death. They are looking at both the neurotrophic effects of estrogen (its ability to promote neuron survival) and its neuroprotective effects (its ability to protect neurons from toxic substances).

The UW research suggests that estrogen acts on neurons differently from its action on cells in other parts of the body.

Among its neurotrophic effects, estrogen may promote the expression of certain neurotransmitter genes by activating an enzyme called protein kinase A. This enzyme promotes a chemical modification of a molecule called CREB (cyclic AMP-response element binding protein), found in the nucleus of brain cells, activating it and allowing certain genes to be expressed in the brain.

Thus, estrogen may increase the amount of particular neurochemicals used by neurons to communicate with one another, such as vasopressin and acetylcholine, known to facilitate learning and memory.

Among the hormone's neuroprotective effects, when neurons are placed in cultures, the addition of estrogen protects them from cell death from toxic agents such as beta amyloid, a protein found in the brains of Alzheimer's patients, which is thought to kill neurons.

As part of this neuroprotective effect, estrogen may mimic or amplify the effects of growth factors produced in the brain. "We know that hormones have a dramatic effect on the viability and growth of the developing brain of the fetus," said Dorsa. "We find the same effects in the aging brain."

UW studies just published in the journal Endocrinology, using chemically modified estrogen that cannot enter cells, suggest that the action may take place at the level of the cell membrane.

"These and other studies are letting us begin to understand at the cellular level how estrogen may act in the brain to reduce the incidence and/or progression of Alzheimer's disease," said Dorsa.

The UW studies, now in their third year of five, are funded by the National Institute on Aging. Besides Dorsa, UW researchers are Cherie A. Singer, Pamela J. McMillan, Jyoti J. Watters, Patricia A. Pang, Dorcas J. Dobie, Keith L. Rogers, Tamara M. Strickland, Jean S. Campbell, Matthew J. Cunningham and Edwin G. Krebs.

University of Washington

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