{"id":8592,"date":"2022-11-01T09:28:27","date_gmt":"2022-11-01T14:28:27","guid":{"rendered":"https:\/\/www.wisconsin.edu\/all-in-wisconsin-new\/?post_type=campus_story&p=8592"},"modified":"2022-11-01T09:28:27","modified_gmt":"2022-11-01T14:28:27","slug":"uwm-research-why-estrogen-decreases-the-risk-of-alzheimers-in-some-menopausal-women-but-not-others","status":"publish","type":"campus_story","link":"https:\/\/www.wisconsin.edu\/all-in-wisconsin\/story\/uwm-research-why-estrogen-decreases-the-risk-of-alzheimers-in-some-menopausal-women-but-not-others\/","title":{"rendered":"UWM research: Why estrogen decreases the risk of Alzheimer\u2019s in some menopausal women, but not others"},"content":{"rendered":"
\"Photo<\/a>
Karyn Frick (seated) and members of her lab \u2013 Miranda Schwabe (from left), Gustavo Dalto Barroso Machado, Sarah Beamish and Farah Abdelazim \u2013 have recently published research that shows why some women with Alzheimer\u2019s disease benefit from taking estrogen therapy, while others do not. (UWM Photo\/Troye Fox)<\/figcaption><\/figure>\n

The hormone estrogen is essential for proper functioning of memory, but it declines when women reach menopause, putting them at a higher risk than men of developing Alzheimer\u2019s disease.<\/p>\n

However, studies of estrogen therapy show the hormone improves brain function in some menopausal women, but not others.<\/p>\n

Working from previous research on late-stage Alzheimer\u2019s, a research team at the University of Wisconsin-Milwaukee has found new information that points to the reason.<\/p>\n

Those at highest risk for developing the disease are over age 60, female and carry a specific variant of a gene that everyone has, called APOE. The gene codes for a protein that captures lipids in the bloodstream and carries them into cells for disposal.<\/p>\n

Three variants<\/h3>\n

UWM distinguished professor of psychology Karyn Frick and her lab members investigated three APOE gene variants and found insight into how different variants of the gene put women at different odds of developing Alzheimer\u2019s.<\/p>\n

A gene often has multiple versions, meaning their arrangement on a DNA strand varies, resulting in different traits, such as eye color. Most variants do not lead to development of disease.<\/p>\n

But, in the case of the APOE variants, one \u2013 called E2 \u2013 is protective in terms of Alzheimer\u2019s risk; another \u2013 called E3 \u2013 is neutral; and a third \u2013 E4 \u2013 increases Alzheimer\u2019s risk.<\/p>\n

Every person carries two APOE variants, and those with two E4 variants are at greatest risk of Alzheimer\u2019s. Frick\u2019s team confirmed this when they tested older female mice and found that animals with two copies of E4 did not respond to estrogen treatment cognitively, but those with one or two copies of E3 did.<\/p>\n

Poor performer<\/h3>\n

The UWM researchers think that the E4 variant may contribute to Alzheimer\u2019s by poorly performing the gene\u2019s main task of transporting lipids into cells for disposal or conversion into other substances.<\/p>\n

\u201cE4 doesn\u2019t do as good a job of clearing lipids and carrying them into cells as E3 and E2,\u201d Frick said. \u201cThat\u2019s important because amyloid, a protein that builds up to toxic levels in the Alzheimer\u2019s brain, is a lipid whose disposal by APOE is essential for maintaining brain health.\u201d<\/p>\n

She called it a two-pronged problem for women because hormones like estrogens are made from cholesterol \u2013 a lipid which must be ushered into cells so that estrogens can be made in the brain. Because E4 doesn\u2019t transport lipids into cells as well as other APOE variants, this can lead to a reduction in cellular estrogen available to the brain, she added.<\/p>\n

\u201cNow that we can model this reduced response to estrogen in mice with two copies of E4, we can better understand why women E4 carriers don\u2019t benefit cognitively from estrogen therapy and we can develop treatments that may specifically benefit those women,\u201d she said.<\/p>\n

The\u00a0study was published\u00a0<\/a>\u00a0recently in the journal Neurobiology of Aging.<\/p>\n

Testing three options<\/h3>\n

The researchers tested what happened when a potent form of estrogen, called estradiol, was given to mice in three groups: those with two copies of E3, those with two copies of E4, and those with one copy of E3 and one copy of E4. Estradiol was delivered directly into a part of the brain called the hippocampus that\u2019s one of the first brain regions to deteriorate in Alzheimer\u2019s.<\/p>\n

They discovered that two copies of E4 inhibited estradiol\u2019s ability to enhance memory for the location and identity of objects, and to improve neuron communication by promoting connectors called \u201cdendritic spines.\u201d In contrast, estradiol improved memory and increased the density of dendritic spines in the hippocampus of mice with one or two copies of E3.<\/p>\n

Dendritic spines are knob-like structures that proliferate along dendrites, the \u201ccommunication lines\u201d on neurons. Neurons connect to each other at dendritic spines, so a loss of dendritic spines reduces communication in the brain. In an Alzheimer\u2019s brain, spines in the hippocampus disappear first, making it an early indication of cognitive decline.<\/p>\n

Another take-home from the study, Frick said, is that for women considering estrogen therapy, knowing their APOE variant composition could help them decide whether to take estrogen therapy for memory protection. Many women are reluctant to take hormone therapy, whether it be for memory protection or to ease bothersome menopausal symptoms, because estrogen could increase their risk of breast or uterine cancer.<\/p>\n

That concern is what led Frick to develop an estrogen compound that would help boost memory without harmful side effects. With colleagues from Concordia University Wisconsin and Marquette University, she formed the startup Estrigenix Therapeutics Inc. with the aim of commercializing compounds that provide the benefits of estrogens without risky side effects.<\/p>\n

Grant from Alzheimer\u2019s Association<\/h3>\n

Meanwhile, Frick\u2019s lab recently landed a new $300,000 grant from the Alzheimer\u2019s Association to take the work a step further. Using their Alzheimer\u2019s mouse model, the researchers will compare effects on memory, dendritic spines and Alzheimer\u2019s pathology of long-term oral treatment with estradiol and two novel estrogen compounds in animals that have the APOE variants E3\/E4 and E4\/E4.<\/p>\n

These novel compounds target another part needed to solve the Alzheimer\u2019s puzzle in women \u2013 estrogen receptors.<\/p>\n

Estrogens influence cell function by binding to estrogen receptors \u2013 including receptors alpha and beta \u2013 inside cells. The alpha receptor, but not the beta receptor, is associated with the cancer-causing effects of estrogen therapy, so Frick\u2019s team at Estrigenix has focused on creating highly selective compounds to target the beta receptor.<\/p>\n

For E4\/E4 animals that have shown no effects to estrogen treatment, the problem could lie with the alpha receptor, Frick said. The researchers have seen an elevated number of alpha receptors in E4\/E4 animals.<\/p>\n

Digging up clues<\/h3>\n

\u201cWe don\u2019t know why that is, but it may hold some clues as to why those animals aren\u2019t responsive to estradiol,\u201d she said. \u201cSo, we\u2019ll be testing estradiol, which binds to both alpha and beta receptors, and then compare those effects to compounds that selectively activate just alpha or just beta, including one of Estrigenix\u2019s compounds. These data could give us a sense of which treatments might benefit women of different gene variants.\u201d<\/p>\n

Unlike the recently published study, animals in the new research will be treated orally for two months, instead of receiving estradiol infusions directly to the brain. Because the new study will use a treatment method that is similar to the one used in people, this work could help makes new treatments available for women more quickly, Frick said.<\/p>\n

Members of the research team also included Lisa R. Taxier, Sarah M. Philippi and Aaron W. Fleischer at UWM, and Jason M. York and Mary Jo LaDu at the University of Illinois, Chicago.<\/em><\/p>\n

\n

Written by Laura Otto<\/p>\n

Link to original story: https:\/\/uwm.edu\/news\/why-estrogen-decreases-the-risk-of-alzheimers-in-some-menopausal-women-but-not-others\/<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

The hormone estrogen is essential for proper functioning of memory, but it declines when women reach menopause, putting them at a higher risk than men of developing Alzheimer\u2019s disease. However, studies of estrogen therapy show the hormone improves brain function in some menopausal women, but not others. Working from previous research on late-stage Alzheimer\u2019s, a […]<\/p>\n","protected":false},"author":15,"featured_media":8595,"comment_status":"closed","ping_status":"closed","template":"","institution":[107],"story_category":[],"class_list":["post-8592","campus_story","type-campus_story","status-publish","has-post-thumbnail","hentry","institution-uw-milwaukee"],"_links":{"self":[{"href":"https:\/\/www.wisconsin.edu\/all-in-wisconsin\/wp-json\/wp\/v2\/campus_story\/8592","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.wisconsin.edu\/all-in-wisconsin\/wp-json\/wp\/v2\/campus_story"}],"about":[{"href":"https:\/\/www.wisconsin.edu\/all-in-wisconsin\/wp-json\/wp\/v2\/types\/campus_story"}],"author":[{"embeddable":true,"href":"https:\/\/www.wisconsin.edu\/all-in-wisconsin\/wp-json\/wp\/v2\/users\/15"}],"replies":[{"embeddable":true,"href":"https:\/\/www.wisconsin.edu\/all-in-wisconsin\/wp-json\/wp\/v2\/comments?post=8592"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.wisconsin.edu\/all-in-wisconsin\/wp-json\/wp\/v2\/media\/8595"}],"wp:attachment":[{"href":"https:\/\/www.wisconsin.edu\/all-in-wisconsin\/wp-json\/wp\/v2\/media?parent=8592"}],"wp:term":[{"taxonomy":"institution","embeddable":true,"href":"https:\/\/www.wisconsin.edu\/all-in-wisconsin\/wp-json\/wp\/v2\/institution?post=8592"},{"taxonomy":"story_category","embeddable":true,"href":"https:\/\/www.wisconsin.edu\/all-in-wisconsin\/wp-json\/wp\/v2\/story_category?post=8592"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}