In the brain, cholinergic neurons play an essential role in learning and attention and these cells are particularly vulnerable in Alzheimer's disease.
Female gonadal hormone estrogen alters the function of cholinergic neurons and is thought to exert ameliorative effects on these cells.
Restoring estrogen levels with hormone replacement therapy (HRT) at the time of menopause appears to reduce the risks of Alzheimer's disease.
However HRT is also associated with detrimental effects such as stroke or cancer, raising concern about its overall safety.
Resolving this conundrum through the selective activation of estrogen-related ameliorative effects in the absence of deleterious consequences would have important implications for treatment of several neurological disorders like Alzheimer's disease.
One strategy to address this issue has been to develop synthetic compounds with selective protective properties of estrogen. A promising recent advance was the discovery of estren - a compound that selectively activates the estrogen related ameliorative mechanisms without any notable side effects.
In our research we test whether estren has ameliorative effect on cholinergic cells in the brain.
In our particular experiments beta-amyloid, a neurotoxin produced in excessive amounts in Alzheimer's disease, is used to elicit cholinergic cell death. Test and control groups are also administered estren, or vehicle, respectively.
Rates of survival of cholinergic neurons are assessed by identifying the cells using immunohistochemistry and cell counting with objective methods such as computerized image analysis.
We test whether estren action depends on estrogen receptor (ER), by repeating the experiments using transgenics that lack functional genes encoding ER. Finally, possible molecular mechanisms of protection are examined by determining the activation patterns of specific signalling molecules, calcium and antiapoptotic proteins with immunohistochemistry and calcium imaging..
Our project recently received support from Neurological Foundation of New Zealand. We hope that our research will contribute to the development of a novel therapy for Alzheimer's disease.
- Dr Istvan Abraham, Lecturer, Department of Physiology.