The hormone estrogen helps protect memory and promote a healthy brain, but this effect wanes as women age, and even estrogen replacement therapy stops working in humans after age 65. Now researchers at University of Florida Health have used gene therapy in a rat model to show that the expression of a particular receptor can reinstate lost memory function.
The scientists, including Thomas C. Foster, Ph.D., a professor of neuroscience and the Evelyn F. McKnight chair for research on cognitive aging, and Linda A. Bean, Ph.D., report their findings in the current edition of The Journal of Neuroscience.
“There is a window of time, starting around menopause, when initiation of hormone replacement therapy with estrogen protects the brain against injury and Alzheimer’s disease. However, this window seems to end around age 65,” Foster said. “We wanted to find out what is regulating this window.”
The researchers used gene therapy to overexpress two different estrogen receptors found in the hippocampus, a part of the brain essential to memory regulation. They found that an abundance of one of these receptors, called alpha, reinstated memory in aging rats when paired with estrogen.
Estrogen helps to do this by increasing the brain’s “plasticity,” which is the ability to form and maintain connections between brain cells as things are learned. As plasticity declines, so do the number of connections in the brain, and certain types of memories begin to fade. Without the protective effect of estrogen, women may lose brain plasticity and start forgetting things more often. The loss of estrogen’s protective effects may explain why women are more likely than men to develop dysfunctional memory problems such as Alzheimer’s disease.
The researchers looked at the effects on memory in six groups, which received gene therapy for expression of the alpha receptor, the beta receptor or a control gene. The three different gene therapy groups then received estrogen or a placebo for the next several weeks, until memory testing and examination of brain plasticity. The project involved 72 animals. Only the group with gene therapy for the alpha receptor plus estrogen showed any beneficial effects on memory and increased brain plasticity markers.
“In the short term, this finding helps us understand how estrogen rescues memory and keeps the brain young and plastic,” Foster said. “In the long term, this finding may eventually allow us to bypass estrogen and target the receptor or brain plasticity mechanisms directly.”
Next steps will include examining the alpha receptor more closely.
“Now that we know this has an effect, we can look for potential ways to treat cognition without hormone replacement,” Foster said.
About this memory and genetics research
Source: Rossana Passaniti – University of Florida Image Source: The image is in the public domain Original Research:Abstract for “Re-Opening the Critical Window for Estrogen Therapy” by Linda A. Bean, Ashok Kumar, Asha Rani, Mike Guidi, Awilda M. Rosario, Pedro E. Cruz, Todd E. Golde, and Thomas C. Foster in Journal of Neuroscience. Published online December 9 2015 doi:10.1523/JNEUROSCI.1890-15.2015
Re-Opening the Critical Window for Estrogen Therapy
A decline in estradiol (E2)-mediated cognitive benefits denotes a critical window for the therapeutic effects of E2, but the mechanism for closing of the critical window is unknown. We hypothesized that upregulating the expression of estrogen receptor α (ERα) or estrogen receptor β (ERβ) in the hippocampus of aged animals would restore the therapeutic potential of E2 treatments and rejuvenate E2-induced hippocampal plasticity. Female rats (15 months) were ovariectomized, and, 14 weeks later, adeno-associated viral vectors were used to express ERα, ERβ, or green fluorescent protein (GFP) in the CA1 region of the dorsal hippocampus. Animals were subsequently treated for 5 weeks with cyclic injections of 17β-estradiol-3-benzoate (EB, 10 μg) or oil vehicle. Spatial memory was examined 48 h after EB/oil treatment. EB treatment in the GFP (GFP + EB) and ERβ (ERβ + EB) groups failed to improve episodic spatial memory relative to oil-treated animals, indicating closing of the critical window. Expression of ERβ failed to improve cognition and was associated with a modest learning impairment. Cognitive benefits were specific to animals expressing ERα that received EB treatment (ERα + EB), such that memory was improved relative to ERα + oil and GFP + EB. Similarly, ERα + EB animals exhibited enhanced NMDAR-mediated synaptic transmission compared with the ERα + oil and GFP + EB groups. This is the first demonstration that the window for E2-mediated benefits on cognition and hippocampal E2 responsiveness can be reinstated by increased expression of ERα.
SIGNIFICANCE STATEMENT Estradiol is neuroprotective, promotes synaptic plasticity in the hippocampus, and protects against cognitive decline associated with aging and neurodegenerative diseases. However, animal models and clinical studies indicate a critical window for the therapeutic treatment such that the beneficial effects are lost with advanced age and/or with extended hormone deprivation. We used gene therapy to upregulate expression of the estrogen receptors ERα and ERβ and demonstrate that the window for estradiol’s beneficial effects on memory and hippocampal synaptic function can be reinstated by enhancing the expression of ERα. Our findings suggest that the activity of ERα controls the therapeutic window by regulating synaptic plasticity mechanisms involved in memory.
“Re-Opening the Critical Window for Estrogen Therapy” by Linda A. Bean, Ashok Kumar, Asha Rani, Mike Guidi, Awilda M. Rosario, Pedro E. Cruz, Todd E. Golde, and Thomas C. Foster in Journal of Neuroscience. Published online December 9 2015 doi:10.1523/JNEUROSCI.1890-15.2015