Animal Studies Indicate Aging Brain Responsive To Estrogen

November 20, 1996

WASHINGTON -- Duke researchers have found that aging female rats treated with estrogen show more connections in a brain area associated with memory formation than did similar untreated rats. The scientists believe their finding offers evidence that minor memory losses sometimes associated with aging might be alleviated by replacing estrogens.

The authors of the study, Phillippa Henderson, Christina Williams and Gillian Einstein, prepared their findings for presentation Friday (Nov. 15) at the Society for Neuroscience meeting.

Henderson is a medical student at the Duke University Medical Center; Williams is an associate professor in the department of psychology -- experimental, and Einstein is an assistant research professor in the medical center's department of neurobiology. Their research was sponsored by the American Foundation for Aging Research, the National Institute for Aging, and the Alzheimer's Association.

Although they are working with aging rats, their findings may have implications for the many post-menopausal women now on estrogen replacement therapy, Williams said.

"While most people are aware that estrogen treatment acts on cholesterol synthesis and bone growth," Williams noted, "they are unaware that it acts on the brain as well."

Information is lacking on such effects, she said, because "living for another 25 or 30 years after menopause is a very recent phenomenon in the history of humankind. Aging without estrogen may be the natural state, but it also may be like the loss of any other hormone. Perhaps what you should do is replace it."

Einstein said their research also suggests a possible mechanism to explain recent findings that women on hormone replacement therapy, and with a family history of Alzheimer's disease, are less likely than their untreated siblings to get the disease. The Duke scientists theorized that treating Alzheimer's patients with estrogens might help protect against neuronal death that leads to the cognitive decline.

"Estrogen replacement therapy might 'shore up' the synaptic connections of neurons affected by the disease," said Einstein.

Earlier behavioral findings from Williams' lab had already shown that older female rats' spatial memory is improved by estrogens administered in a cyclic fashion. These findings led to the cellular studies in Einstein's lab that now suggest a mechanism for this improvement in memory.

In the study, the team used aging female rats that had their ovaries removed and, thus, were making no estrogen. The researchers divided the rats into three treatment groups -- those receiving no estrogens, long-term chronic estrogen doses, or a single acute dose of estrogen.

After the treatments, they performed microscopic studies that allowed them to determine how the treatments affected neurons called granule cells in the rats' hippocampus, a brain region involved in spatial memory. The scientists' study of single neurons revealed that the rats exposed to acute estrogen treatment had 40 percent more connective elements, called "dendritic spines," on these neurons than did aged female rats with no estrogen replacement or those exposed to long-term chronic estrogens. Dendritic spines may be the basis for the brain's ability to develop new memories, the scientists said.

"These studies suggest that the hippocampus of the female rat responds best if it is exposed to estrogen in cyclical fashion, as is the case in young adult female rats," Williams said in an interview. "Giving aging females estrogen in a constant fashion was no better for their brain than giving no estrogen at all.

"We're not yet sure whether this is also true in males, and one of our next steps is to determine if neurons in aged males are responsive to estrogens as well. They may or may not be since, paradoxically, males have estrogens in their brains naturally throughout life, because testosterone is converted in the brain into a form of estrogen called estradiol."

Given that estrogen-enhanced dendritic growth, even in the aged brain, and that Alzheimer's disease is marked by loss of new dendrites, these findings suggest that estrogens might help protect against neuronal death in Alzheimer's disease, said Einstein.

The researchers believe that such findings as theirs indicate the need for much more study of the neurological effects of estrogen on both females and males.

"There's been considerable study of what estrogen is doing for the bones and the heart in aging, but not so much about what estrogens are doing for the brain," Einstein said. The scientists also said they believe their findings demonstrate the need to take brain effects and the timing of doses into account when considering hormone replacement therapy.
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Duke University

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