By David N. Leff

While the feminist movement - by demanding equal opportunity for men and women - greatly narrowed the gender gap in recent decades, Mother Nature herself remains guilty of gross political incorrectitude.

As the onset of menopause - around 50 or 51 years of age in the U.S. - signals the shutdown of her reproductive capacity, a woman suffers various discomforts and disorders, notably hot flashes. These coincide with the waning of the hormone estrogen (called by some "the juice of life") as menopausal ovaries turn off the tap on its secretion.

That estrogen loss with advancing age increases the likelihood of osteoporosis (bone fragility) and heart disease. Estrogen replacement medication fends off these maladies. It lowers the risk of heart disease by half. But that supplemental estrogen also increases the risk of endometrial (uterine) cancer, and breast cancer malignancy as well. Menopause is a win-lose fact of female life.

But recent evidence adds another plus to these minuses: Estrogen replacement also seems to reduce by 50 percent the chance of a woman getting Alzheimer's disease (AD).

"In a retrospective study," observed neuroscientist Paul Greengard, "postmenopausal women had twice the incidence of AD as did men of the same age. It showed that in women given estrogen to prevent osteoporosis, the AD rate was reduced to that of the men. Compared to placebo controls, it was less by 50 percent." (See BioWorld Today, April 8, 1998, p. 1.)

Greengard heads the Laboratory of Molecular and Cellular Neuroscience at The Rockefeller University, in New York, and directs its Fisher Alzheimer Research Center. "We found the molecular basis for this estrogen/Alzheimer connection a year or two ago," he recalled. "We showed that estrogen given to human or rat fetal brain cells reduced the amount of beta amyloid - the peptide that makes senile neuritic plaques, the unique hallmark of AD. And the amount of the innocuous APP segment - precursor of the beta amyloid - was increased."

Enzymes Carve Plaque Stuff Off Parent Molecule

APP - amyloid precursor protein - is a ubiquitous molecule, 700 amino acids long, inside human cells, including brain neurons. It can be converted by proteolytic cleavage either into plaque-forming beta amyloid or harmless, soluble APP. Enzymes called secretases chop off a small segment of APP, which makes those plaques outside the neuron - as well as similar, benign fragments - and then those pieces are released. So the sAPP goes up and the beta amyloid goes down.

"From the clinical point of view," Greengard pointed out, "what goes wrong is that when a secretase enzyme forms beta amyloid by cleaving the APP, that beta amyloid destroys the nerve cells, particularly in the memory and cognition centers of the brain, and this produces dementia associated with AD.

"So then," he continued, "we decided to see whether testosterone, which is chemically related to estrogen, might have a similar effect. And we found that it did. Here we used just cultured neurons from rats and mice, but no human tissues. We found that testosterone does the same thing as estrogen. Treatment with testosterone incubated for 10 days with those rodent neurons increased their beta-amyloid peptides by 30 to 45 percent."

Greengard is senior author of a paper reporting this work in the current issue of the Proceedings of the National Academy of Sciences (PNAS), dated Feb. 1, 2000. Its title: "Testosterone reduces neuronal secretion of Alzheimer's b-amyloid peptides."

"In that paper," he told BioWorld Today, "we suggest the possibility that testosterone treatment for aging men be considered. In other words," Greengard explained, "men don't go through this abrupt menopause that women do. Rather, they experience a gradual decreased secretion of testosterone over the decades. So the suggestion we made is that for men at high risk of AD, such as people with the APOE4 gene, one might give them replacement testosterone. But you've got to balance that against the risk of their getting prostate cancer. If I knew I had APOE4," he went on, "I would be inclined to take my risks, but I don't know what the FDA would say, or what clinicians would be willing to do, and I'm not going around proselytizing people to do it either."

The Rockefeller neuroscientist and his co-authors are now about to move up from cultured rat cells to preclinical trials, using transgenic mice. "We're planning to do a series in whole animals," he said, "to see if, by giving testosterone we can reduce the amount of beta amyloid formed. We'll probably use transgenic mice, for which there are various possibilities. There are mutations in the APP protein that make it much more susceptible to forming beta amyloid. We'll put this mutated form of APP - which is responsible for early-onset AD in humans - into the mice. Then we will study the effect of testosterone on their formation of beta amyloid. That's our plan."

Oral Drug Outlook 'Hopeful'

For people concerned about possible AD in their elderly relatives, and for the neurologists who see them, Greengard proposed, based on his research: "I think the main take-home message is that whether or not testosterone is tested in the clinic, the important thing is that we, together with a number of other laboratories, are beginning to understand the pathways that regulate the formation of beta amyloid, and this gives us great hope that drugs to treat AD will be found. And as we elucidate these biochemical pathways, that they will provide targets for the development of compounds that prevent the formation of beta amyloid.

"One way such an agent might work," he speculated, "would be by inhibiting the secretase enzymes. Another way would be accelerating the trafficking of APP through the cells, so it would have less exposure time to be degraded by the enzyme. And there's no reason to believe that one couldn't develop orally available drugs.

No Comments