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Neuroprotection
Estradiol has a positive neuroprotective influence on neurons. Two neuroprotective qualities conferred by this hormone are increased mitochondrial function and protection against amyloid-β protein-induced toxicity, both of which are mediated by estrogen receptors. The mechanisms by which this hormone exerts its neuroprotective effects are not yet fully understood. A better understanding of how estradiol serves as a neuroprotective agent may lead to improved treatment options for Alzheimer's disease and menopause, ,.

Estrogen receptors
The main targets of estradiol in the brain are the hypothalamus and the pituitary gland. These regions interact with estradiol and play a role in menstrual cycle regulation but are not involved in neuroprotection.

The estrogen receptors involved in neuroprotection are located in the hippocampus and the frontal lobes, two areas responsible for various types of memory. Estradiol treatment improves performance on memory tests, ,. Two types of estrogen receptors exist, estrogen receptor-αs and estrogen receptor-βs. Both types of receptors exert their effects via transcriptional regulation in the nucleus.

Amyloid-β protein accumulation in the hippocampus, commonly seen in Alzheimer’s disease, is reduced by estradiol treatment,. The reduction of amyloid-β protein levels is mediated by the estrogen receptors. Selective estrogen receptor modulators have been used to determine the individual involvement of the estrogen receptor-αs and estrogen receptor-βs in the lowered amyloid-β protein levels. The selective estrogen receptor modulator propylpyrazole triol activates only estrogen receptor-αs and the selective estrogen receptor modulator diarylpropionitrile activates only estrogen receptor-βs. Propylpyrazole triol reduces amyloid-β protein levels but diarylpropionitrile does not, showing that the estrogen receptor-αs mediate the reduction of amyloid-β protein levels but estrogen receptor-βs do not. The estrogen receptor-αs do so by activating seladin-1, a neuroprotective gene that reduces β-amyloid protein accumulation.

Mitochondria
Neurons require an immense amount of energy in the form of ATP in order to carry out their functions. Between 60-80% of the energy is dedicated to maintaining ion gradients across cell membranes via sodium, potassium and calcium ATPase pumps. These ion concentration gradients are crucial for signal transduction between neurons. Mitochondria must be active and function efficiently in order to produce enough ATP to support the energy needs of neurons.

Estradiol has positive effects on brain mitochondria, specifically causing increased mitochondrial respiration, increased cytochrome c reductase levels, and decreased reactive oxygen species levels,. Estradiol leads to increased activity of the electron transport chain in brain mitochondria, resulting in more ATP production and more efficient signal transduction. Treatment with estradiol also causes mitochondrial respiration to increase by 13%, signifying that estradiol treatment leads to more active mitochondria.

Cytochrome c reductase is a protein in the electron transport chain. The level of cytochrome c reductase can be assayed and used as an indicator of the activity of the electron transport chain. Estradiol treatment leads to a significant increase in the level of cytochrome c reductase, meaning the electron transport chains in the estradiol-treated cells are more active than the untreated ones,. The elevated cytochrome c reductase levels are mediated by the estrogen receptor- αs but not the estrogen receptor- βs.

Estradiol treatment results in a reduced level of reactive oxygen species,. The lower level of reactive oxygen species seen after estradiol treatment is a result of the increased amount of cytochrome c reductase. The decreased levels of reactive oxygen species is also caused by elevated amounts of manganese superoxide dismutase, a mitochondrial antioxidant protein. Manganese superoxide dismutase is responsible for converting reactive oxygen species into less harmful compounds, such as hydrogen peroxide and oxygen.

Menopause
Menopause is characterized by a dramatic reduction in the ovarian production of estradiol. A decline in cognitive ability and an increased risk of neurodegenerative disease development are commonly seen in post-menopausal women. Menopausal women who receive hormone replacement therapy perform better on figural memory tests because the hormones have a neuroprotective effect. However, hormone replacement therapy can have detrimental side effects in women that outweigh the benefits, such as increased incidence of breast cancer and stroke.

A combination of select phytoestrogens confers the neuroprotective effects of estradiol without the dangerous side effects commonly seen in hormone replacement therapy. The phytoestrogens, genistein, daidzein, and equol lead to increased mitochondrial respiration and cytochrome c reductase levels when used in combination. The binding affinity of these compounds is currently only 40% of the binding affinity of estradiol. Increasing the binding affinity could make the use of phytoestrogens a common and safe alternative to hormone replacement therapy in menopausal women.

Alzheimer's disease
Estradiol treatment leads to less hippocampal β-amyloid protein accumulation in Alzheimer’s disease models as well as improved performance on hippocampal-dependent memory tasks,. Selective estrogen receptor modulators that activate the estrogen receptor-αs, such as propylpyrazole triol, have the same positive effects on hippocampal β-amyloid protein levels and hippocampal function as estradiol,. Selective estrogen receptor modulators that activate the estrogen receptor-βs, such as diarylpropionitrile, do not confer the same effects as estradiol treatment. Estradiol lowers hippocampal β-amyloid protein levels and improves performance on hippocampal-dependent tasks via the estrogen receptor-αs. Selective estrogen receptor modulators that target the estrogen receptor-αs may be used to treat Alzheimer’s disease in the future because they do not cause the negative side effects that accompany hormone replacement therapy, such as increased risk of breast cancer,.