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Senior Scholar Award in Aging
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Phyllis M.
Wise,
Ph.D.
University of California - Davis
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Estradiol is a Neuroprotective Factor in the Aging Brain: Mechanisms of Action
Estrogen appears to protect the aging brain against cognitive dysfunction,
neurodegenerative diseases, and brain injury such as stroke. The menopause is
accompanied by a dramatic and permanent decrease in estrogen levels. During the past
century, the longevity of women has increased from 50 to over 80 years. But, the age of
the menopause has remained constant and occurs when women are about 50 years of
age. This means that after women undergo the menopause, they will be hypoestrogenic
for over thirty years of their lives, and may consequently suffer from an increased
vulnerability to a variety of diseases. It is, therefore, crucial that we understand how
estradiol acts to protect the brain against these diseases so that we can design drugs that
exert only protective actions of estradiol, and do not have detrimental side effects. Since
high doses of estradiol can have unwanted side effects, the longterm goal of our studies is
to understand the molecular mechanisms by which low, physiological levels of estradiol
replacement protect the brain.
We have previously discovered that low levels of estradiol replacement exert profound
protective effects in the brain. Using an animal model of stroke, we found that estradiol
dramatically decreases the degree of brain injury in adult and in aging female rats.
Therefore, the proposed studies are designed to uncover how estradiol acts to protect the
brain. First, we will assess the molecular mechanisms of estradiol’s protective actions in
vivo using wild-type and ER*KO mice combined with DNA array technology. This
specific aim seeks to identify the repertoire of genes that are influenced by estradiol in a
model of brain injury. Second, we will determine whether the neuroprotective actions of
estradiol in in vitro explant cultures of the cerebral cortex of wild-type and ER*KO mice
parallel in vivo observations. We will use explant cultures of cerebral cortex to determine
whether we can replicate estradiol’s protective actions in an in vitro model of brain
injury. Third, we will verify changes in gene statement detected through array technology
using in situ hybridization and real-time PCR methods. It is clear that this new and
powerful method must be verified using other methods before data can be considered
trustworthy. Finally, we will assess whether estradiol’s protective effects result from
receptor-mediated actions on neurons or astrocytes by using the Cre-Lox mouse system
to selectively knockout ER in neurons or astrocytes.
In summary, our proposed studies focus on novel, non-reproductive actions of estradiol
in the brain. The results will provide new information regarding mechanisms underlying
estradiol-dependent enhancement of neuronal viability. They carry profound and exciting
possibilities in the future treatment of brain injury and cognitive disorders in elderly
women.
Contact
Dr. Wise.
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