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Reproductive Sciences-2016-Rao-1933719116658705

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Reproductive Sciences-2016-Rao-1933719116658705

  1. 1. Review Involvement of Luteinizing Hormone in Alzheimer Disease Development in Elderly Women C. V. Rao, PhD1,2,3 Abstract Alzheimer disease (AD) is a slow progressive neurodegenerative disease that affects more elderly women than elderly men. It impairs memory, typically progresses into multidomain cognitive decline that destroys the quality of life, and ultimately leads to death. About 5.3 million older Americans are now living with this disease, and this number is projected to rise to 14 million by 2050. Annual health-care costs in the United States alone are projected to increase to about US$1.1 trillion by 2050. The initial theory that decreasing estrogen levels leads to AD development in postmenopausal women has been proven inconclusive. For example, Women’s Health Research Initiative Memory Study and the population-based nested case–control study have failed to demonstrate that estrogen/progesterone (hormone replacement therapy [HRT]) or estrogen replacement therapy could prevent the cognitive decline or reduce the risk of AD. This led to the realization that AD development could be due to a progressive increase in luteinizing hormone (LH) levels in postmenopausal women. Accordingly, a large number of studies have demonstrated that an increase in LH levels is positively correlated with neuropathological, behavioral, and cognitive changes in AD. In addition, LH has been shown to promote amyloidogenic pathway of precursor protein metabolism and deposition of amyloid b plaques in the hippocampus, a region involved in AD. Cognate receptors that mediate LH effects are abundantly expressed in the hippo- campus. Reducing the LH levels by treatment with gonadotropin-releasing hormone agonists could provide therapeutic benefits. Despite these advances, many questions remain and require further research. Keywords Alzheimer disease, luteinizing hormone, estrogens, androgens, LH/hCG receptors, Ab plaques, neurofibrillary tangles Introduction Alzheimer disease (AD) is a neurodegenerative disease that primarily affects elderly women.1-3 The disease progression is exceedingly slow and can take decades before the symptoms appear and a clinical diagnosis can be made.1-3 Dementia, which is a decline in cognitive ability and memory loss, is the hallmark feature of AD.1-3 It accounts for more dementias than from any other illnesses, including vascular etiologies. The distinction between them often made by an expert neurolo- gist.1-3 Since some of the AD symptoms overlap with those due to other neurodegenerative diseases and even from taking certain medications, careful clinical history and neurological examination are important for AD diagnosis.1,3 The risk factors, which can influence each person differ- ently, include family history, genetics, heart disease, stroke, high blood pressure, dyslipidemia, low levels of vitamin folate, and so on.1-3,4 Obesity and type 2 diabetes increase the risk 3.0- and 1.5-fold, respectively.1-3,5,6 Only 1% of all cases with AD are inherited.1-3 There are risk (apolipoprotein E4) and deter- ministic (amyloid precursor protein [APP], presenilin 1 and 2) AD genes.7,8 The mutations in deterministic genes cause a rare form of the disease.7,8 Healthy weight maintenance, prevention of type 2 diabetes, exercise, and drinking coffee and red wine in moderation appear to reduce the risks of AD.1-3 Being physically and men- tally active and engaging in social activities can delay the onset and slow the progression of AD.1-3 There are no simple diag- nostic tests.1-3 Position emission tomography (PET), spinal taps to determine brain amyloid b (Ab) levels, and brain 1 Department of Cellular Biology and Pharmacology, Reproduction and Development Program, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA 2 Department of Molecular and Human Genetics, Reproduction and Development Program, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA 3 Department of Obstetrics and Gynecology, Reproduction and Development Program, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA Corresponding Author: C. V. Rao, Departments of Cellular Biology and Pharmacology, Molecular and Human Genetics, and Obstetrics and Gynecology, Reproduction and Development Program, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA. Email: crao@fiu.edu Reproductive Sciences 1-14 ª The Author(s) 2016 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1933719116658705 rs.sagepub.com by guest on July 20, 2016rsx.sagepub.comDownloaded from
  2. 2. imaging can be helpful in the diagnosis of AD.1-3 These tests are expensive and not widely available. Therefore, blood biomarker-based tests, which detect Ab, are being developed. However, unequivocal diagnosis can only be made at autopsy.1-3,9 The incidence of AD is higher among older African and Hispanic than Caucasian Americans.10 The total number of cases with AD is increasing each year in the United States, due to an increase in life expectancy from better health care and the number of people surviving into their 80s, 90s, and beyond. There are mild, moderate, and severe forms of the disease.1-3 Although individuals with mild AD can live up to 25 years, the ones with severe AD typically live for only 5 years.1-3 In severe form of AD, most of the cortex is severely damaged and brain dramatically shrinks due to widespread cell death.1-3 Alzhei- mer disease is one of the top 10 leading causes of death in the United States, sixth leading cause of death among adults, and fifth leading cause of death among 65- to 85-year-old people.1-3 Alzheimer disease is a very expensive disease. For exam- ple, US$226 billion is estimated to cost for AD care in the United States in 2015.11 These costs do not include unpaid care given by family members and friends, which is roughly estimated to be 18 billion hours or about US$218 billion.3 Living with AD is extremely difficult because of pain, suffer- ing, loss of individuals’ dignity, financial setbacks, disruption of families, among others.1-3 Amyloid Plaques and Neurofibrillary Tangles The deposition of Ab protein plaques and formation of neuro- fibrillary tangles of hyperphosphorylated tau proteins in the hippocampus and frontal cortex are hallmark features of AD.12-15 The plaques are formed due to an imbalance between the production and the clearance of Ab from the brain.12,13 The plaques are rather inert and its Ab aggregates promote synaptic dysfunction, disrupt mitochondrial activity, induce cascades of generation of free radicals, cause oxidative damage, increase tau phosphorylation, impair receptor signaling, Ca2þ homeos- tasis, induce membrane depolarization, proinflammatory changes, and so on.12,13 The neurofibrillary tangles consist of intraneuronal paired helical filaments of hyperphosphorylated tau protein. These tau proteins contain more phosphorylation sites and have a higher molecular weight than the normal tau protein.14,16 The tangles interfere with protein and nutrient traffic in neurons.1-3,16,17 Plaques and tangles can also cause an immune response and work synergistically to promote neu- rodegeneration in the brain.12-16 Amyloid bs are formed from APP, a single-pass transmem- brane protein, with a large extracellular domain and a small cytoplasmic tail.17 Amyloid bs are formed by the sequential cleavage at the N-terminal domain by b-secretase, resulting in shedding of APP ectodomain.18 Then, g secretase cleaves membrane-associated APP C-terminus domain, releasing Ab molecules.18 There are 2 forms of Ab molecules, Ab1-40 and Ab1-42.18 They are sticky, but Ab1-42 is more neurotoxic because it aggregates much more rapidly, which facilitate further deposition of Ab molecules.18 The Ab plaques can be cleared from the brain by efflux, phagocytosis, and enzyme degradation by neprilysin and insulin-degrading enzyme (pre- ferential toward insulin).12,13 Neurofibrillary tangles, on the other hand, can disappear due to dissolution.16 Neuroprotective agents, such as estrogens and androgens, promote nonamyloidgenic pathway of APP metabolism in which a-secretase cleaves within Ab domain of APP, prevent- ing the formation of Ab molecules and releasing neuroprotec- tive a-APP fragments.18-20 The neurotoxic agents, such as luteinizing hormone (LH)/human chorionic gonadotropin (hCG), promote amyloidogenic pathway of APP metabolism in which Abs are formed.21,22 The mutations in deterministic genes result in the overproduction and deposition of Ab molecules.7,8 Paradigm Shift on the Actions of LH/hCG Luteinizing hormone and hCG are structural and functional homologs that are secreted by anterior pituitary gland and human placenta, respectively.23 They belong to glycoprotein and cystine-knot growth factor families.23,24 The latter super- family includes nerve growth factor (NGF).24 Luteinizing hor- mone and hCG bind to the same cell surface G-protein-coupled receptors, which are different from the NGF receptors.25,26 According to the old paradigm, LH/hCG receptors are only present in gonads and LH/hCG can only regulate gonadal functions. The paradigm shift has changed this dogma.27 It has revealed that functional LH/hCG receptors are also pres- ent in central and peripheral (spinal cord and adrenal pheo- chromocytoma cells, which have an embryological origin with neural crest) nervous systems among the other nongona- dal tissues.28-30 The LH/hCG receptors have been demonstrated in fetal rat brain and in adult rat, mouse, bovine, and human brains.28,31,32 In fetal rat brains, receptors have been found in diencephalon, mesencephalon, rhombencephalon, and telencephalon.31 The receptors are present in neurons as well as in the glial cells.33,34 The neuronal receptors are involved in neurite outgrowth and their survival.33 The glial cell receptors are involved in the regulation of prostaglandins (PGs) synthesis, which influence cell proliferation.34 The sum of all the LH actions can contrib- ute to growth, development, and differentiation of fetal brains. Adult brain receptors have been well characterized. The receptors were found in hippocampus; dentate gyrus; cerebel- lum; cerebral cortex; hypothalamus; preoptic area; anterior pituitary; choroid plexus; ependymal cells of third, fourth, and lateral ventricles; pineal gland; and brain stem, with the highest levels in rat hippocampus.28,30,32,35 Unlike adults, fetal hippo- campus does not contain higher receptor levels than the other brain areas.31 The receptors were also detected in primary as well as in immortalized cells, such as hypothalamic GT1-7 neurons, a-T3 anterior pituitary gonadotropins, HN33p hippocampal neurons, and so on.36-40 The receptor promoter usage appears to be the same among these cells.41 However, the transacting protein 2 Reproductive Sciences by guest on July 20, 2016rsx.sagepub.comDownloaded from
  3. 3. levels are different, which may explain the receptor level dif- ferences among the cells.41 The functional relevance of adult brain LH/hCG receptors has been investigated by primary GnRH and hippocampal neu- rons as well as by GT1-7, a-T3, and human M17 neuroblas- toma cells. In primary and in GT1-7 cells, hCG inhibited the release of gonadotropin-releasing hormone (GnRH).36,38 This inhibition was due to a decrease in the transcription of GnRH gene in GT1-7 neurons.36 The mechanisms involved downre- gulation of GnRH receptor gene by decreasing the stability of the transcripts and induction of a 95-kDa transacting protein, which binds to AT-rich sequence (À91 to À81 base pair) in the 50 -flanking region of GnRH gene promoter.36,39,42 The induc- tion preceded by an activation of cyclic AMP (cyclic AMP [cAMP])/protein kinase A (PKA) signaling and increase in protein synthesis, phosphor-CREB, c-Fos, and c-Jun lev- els.38,43 Dimer conformation of the hormone and the receptor presence are required for the LH/hCG actions.36 These findings support the presence of short-loop negative feedback mechan- ism in which some of the LH released from anterior pituitary gets back into portal circulation to reach hypothalamus to inhi- bit GnRH release.44-47 The LH/hCG treatment of a-T3 cells resulted in a dose- and time-dependent and hormone-specific increase in gonadotropin a-subunit levels.37,48 As expected, GnRH treatment also increased the gonadotropin-a subunit levels.48 Both LH and GnRH are synergistic, however, they differed in their mechan- ism of action. Thus, while LH acted to increase the stability of gonadotropin-a subunit transcripts, GnRH increased not only the stability of transcripts but also the transcription of the gene.48 The LH actions in a-T3 cells suggest that LH promotes its own synthesis by an ultra-short-loop positive feedback mechanism, and several previous studies have shown its exis- tence.44-47 A similar mechanism has been found for hCG synth- esis in human placenta.49 The neuronal receptors are colocalized with cytochrome P450 side-chain cleavage enzyme (P450scc).32 The LH/hCG receptor activation results in a 2-fold increase in pregneno- lone secretion and an increase in steroidogenic acute regula- tory protein expression in rat primary hippocampal neurons and in human M17 neuroblastoma cells.50,51 These findings suggest that LH and hCG are capable of increasing mitochon- drial cholesterol transport and its subsequent cleavage by P450 scc. Thus, LH/hCG can induce steroid production just as in the gonads. As peripheral macrophages,52-54 central nervous system (CNS) macrophages, that is, glial cells, also contain LH/hCG receptors.34,55 Their activation results in an increase in induci- ble nitric oxide synthesis, mediated by tumor necrosis factor a.55 Glial cells can also synthesize PGs and neurosteroids.34,50 Luteinizing hormone/hCG can stimulate glial cell synthesis of PGs, and whether they can also regulate the synthesis of neu- rosteroids is unknown.34 The hippocampal receptors are involved in behavioral reg- ulation.56-61 Thus, central and peripheral injection of hCG resulted in several behavioral changes, which include: a. decrease in taste neophobia,61 b. increase in non-rapid eye movement sleep (NREM), with no effect on rem (REM) sleep,61 c. decrease in exploratory and increase in resting beha- viors,60,61 and d. decrease in active awake phase, walking, sniffing, and chewing.60 The behavioral changes are similar regardless of the route of injection.61 About 1% of peripherally injected hCG can cross blood barrier and reach cerebrospinal fluid and hippocampus in an intact form.61 Some of the above behavioral changes were considered typical of human pregnancy. Thus, pregnancy- specific behaviors are likely mediated by the increasing hCG levels during the first half of pregnancy. The behavioral hCG effects are blocked by coadministration of indomethacin.60 Moreover, hCG treatment increased prostaglandin D2 (PGD2) and decreased prostaglandin E2 (PGE2) synthesis.60 Treatment of hippocampal HN33p cells resulted in a modest dose- and time-dependent and hormone-specific increase in 5- lipoxygenase levels.40 These findings support that the products of arachidonic acid metabolism mediate the behavioral effects of hCG. Neural retina, which is an extension of CNS, also contains LH/hCG receptors.62,63 The receptor transcript levels are sim- ilar between retina and cerebral cortex.62 Photoreceptor cells contained the highest receptor levels, followed by a gradual decline through inner retinal layers.62 The findings support the previously suspected LH/hCG role in visual processing and in pathological eye conditions.64,65 Different cells in gray and white matter of spinal cord con- tain LH/hCG receptors.29 The receptors seem to mediate the neurotropic effects of hCG.66 Thus, hCG-treated rats showed a possible functional recovery and physiological communication across the spinal cord injured site.67 It is possible that not only the hippocampal LH/hCG recep- tors but also those in the other brain areas could somehow be involved in the complex pathogenesis of AD. Further research is required to verify and extend this possibility. Evidence Implicating LH in AD Development in Elderly Women Estrogens are neuroprotective.68-70 This protection comes from a host of different mechanisms such as reducing the neuronal loss andcerebral ischemia,stimulatingaxonal sprouting,dendrite spine formation,andpromotingnonamyloidgenicpathwayofAPPmeta- bolism.19,68-73 In addition, estrogens levels are positively corre- lated with cognitive performance. Their replacement in women with cognitive impairment results in an improvement.74-100 Spatial memory decreases in ovariectomized rats, but estrogen treatment reversesit.101,102 These findingssuggest that HRT and ERT should preventcognitivedeclineinwomenwhohadanovarianfailure ora natural age-dependent decline in ovarian activity. However, the results of clinical testing were inconclusive.74-100 This could be due to a number of different reasons, and one of them could be the recipient’s age when the treatment began. Rao 3 by guest on July 20, 2016rsx.sagepub.comDownloaded from
  4. 4. The Women’s Health Research Initiative Memory Study (WHIMS) is ancillary to Women’s Health Initiative (WHI) on hormone therapy trials. From 39 of 40 WHI clinical centers, the WHIMS recruited 4894 eligible women (aged 65 years or older) free of dementia.103,104 They were either placed on HRT (n ¼ 2229) or on placebo (n ¼ 2303). Global cognitive function was measured annually.103,104 The results revealed that HRT did not improve cognitive function when compared with pla- cebo group.103,104 Moreover, a subset of women showed a small increased risk of cognitive decline.103 Another study, population-based nested control, revealed that ERT did not reduce AD risk in 112 481 women as compared with a similar number of cohorts who did not use the therapy.105 The studies of this size can be expected to have some uncontrolled vari- ables, which could possibly undermine their conclusions. Nev- ertheless, the bottom line of the studies is that neither HRT nor ERT could prevent cognitive decline or AD development in older women.103-105 The results led to a critical period hypoth- esis as well as initiated a search for other hormonal causes for AD development. According to the critical period hypothesis, while HRT started immediately after menopause could have worked, it becomes detrimental with time delay.106,107 In fact, HRT was administered more than 5 years after the menopause onset in about 36% of women.103,104 The time delay effect can perhaps be explained by neurological damage, which increases with an advancing age of patients with AD. Concerning the other hormonal basis for AD develop- ment, it is well known that ovarian function declines with age, which results in a decrease in estrogen levels and an increase in LH levels, due to a loss of negative feedback mechanism by estrogens.108,109 Therefore, the consequence of estrogens decrease is an increase in LH and/or follicle- stimulating hormone (FSH) levels. However, this possibil- ity received almost no attention until the discovery of hip- pocampal LH/hCG receptors, greater elevation in LH levels in women with AD, and direct LH effects on cogni- tion and biochemical changes typical of AD. The role of FSH is unknown even though its synthesis and receptors have been demonstrated in rat hippocampus.110 Further studies are now required to test the possibility of FSH invol- vement in AD. There were a now many reports demonstrating the role of LH in AD development. These are: – Epidemiological studies have shown that higher LH lev- els parallel an increase in AD risk.4,111 – Circulating LH levels are more than doubled in postme- nopausal women who have developed AD than the cohorts who did not develop the disease or in non-AD patients with cognitive deficits.112,113 – Ovariectomy causes an elevation in Ab levels in cere- brospinal fluid and hippocampus.114 – The reduction in LH levels improves cognition, decreases Ab levels in mouse brain, and prevents mem- ory loss in neurotoxin-induced AD model.21,115-118 – Similar reduction in LH levels in AD models results in a decrease in cognitive deficits.114-116,119 – Blocking LH synthesis improves cognition in an intact AD Tg 2516 mice.116 – Overexpression of LH impairs memory in a mouse AD model.120 – Elevated LH levels correlate with an increased AD risk and progression, cognitive decline, and increased Ab levels.112,113,120-124 – Alzheimer disease brains have a strong immunoreactive LH than the control brains. Moreover, LH accumulates in pyramidal neurons of AD brains compared with the age-matched normal brains.121 – Direct exposure of guinea pig brain to LH results in altered Ab levels.125 – Luteinizing hormone promotes amyloidogenic pathway of APP metabolism, Ab secretion, and its deposition in the aging brain.21 – Human chorionic gonadotropin increases b-secretase activity in a dose-dependent manner.22 The hCG admin- istration leads to an increase in Ab40 accumulation and cognitive deficits in a mouse model of AD.22,126,127 – The same hCG treatment applied even to ovariecto- mized rats results in the disruption of spatial mem- ory and increase in soluble Ab1-40 and Ab1-42 levels.126 – Treatment of AD transgenic mice with gonadotropin releasing hormone analog (GnRHA) decreases Ab deposition and improves working memory.120 – The GnRH analogs (GnRHa) treatment results in a 3.5- fold reduction in Ab1-42 and 1.5-fold reduction in Ab1- 40 levels and improved cognition in the absence of any changes in estrogen receptors (ERs) a and b, cyto- chrome P450 119, and StAR levels.21,115 – The GnRHa treatment, but not HRT, improved hippo- campal spatial memory in 3xTg AD female mice in an advanced stages of the disease.119,120 – The GnRHa treatment upregulates the pathways associ- ated with a cognition improvement such as Ca2+ /calmo- dulin-dependent protein kinase 1 (CAMK 1), glutamate receptor 1 serine residue831 (GluR1Ser831). Estrogens, on the other hand, had no effect.115,119 – Ablation of LH actions through inactivation of LH/hCG receptor gene resulted in a reduced Ab accumulation, plaque formation, and improvement in neuropathologic features in mouse model of APPSWþ /LHrÀ .128 – Infants from Down syndrome pregnancies, who had an in utero exposure to high hCG levels, have an increased prevalence and an early onset of AD.129-131 Luteinizing Hormone Actions in the Peripheral Organs That Can Potentially Contribute to the AD Development Ovaries, adrenal glands, adipose tissue, and pancreas also contain functional LH/hCG receptors.132-136 The LH 4 Reproductive Sciences by guest on July 20, 2016rsx.sagepub.comDownloaded from
  5. 5. actions in them could potentially contribute to AD devel- opment in postmenopausal women through further eleva- tion in LH levels. The LH elevation comes from the estrogen formation from the androgen precursors, which then positively feedback on hypothalamic–pituitary axis to release even more LH (Figure 1). The involvement of ovaries is related to the LH stimulation of stromal cell luteinization and their secretion of andro- gens.137,138 The adrenal involvement is related to the LH sti- mulation of zona fasciculate to secrete androgens.139-141 Adipose tissue involvement is related to an aromatization of ovarian and adrenal-derived androgens.142-144 As obesity is one of the risk factors for the AD devel- opment, it is possible that LH-induced risk involves its fat deposition property.134 For example, LH can stimulate cell proliferation, differentiation, and leptin secretion from pre- adipocytes.134 These actions are mediated by cAMP-/PKA- independent mitogen-activated protein kinase (MAPK)/ c-Fos signaling.134 Obesity decreases sex steroid–binding globulin, which results in an increase in circulating free estradiol levels.145 The free estradiol is a powerful stimu- lus for bioactive LH release from the anterior pituitary.146 The involvement of the pancreas is related to the LH stimu- lation of pancreatic b-cells to release more insulin.135 The increased insulin levels can stimulate proliferation and luteini- zation of ovarian stromal cells, their secretion of androgens, and aromatization in adipose tissue.145,147 The impact of per- ipheral insulin on CNS actions is not known. The sum of all the LH actions in peripheral organs can result in further elevation in LH levels in postmenopausal women who develop AD as compared with cohorts who do not develop the disease. It is not just the elevation in LH levels alone that can cause AD development, as not all postmenopausal women will develop the disease. The subset of women who develop AD must have other predisposing genetic, epigenetic, environ- mental, lifestyle risk factors, and so on. This reasoning should not be surprising as AD, like most other diseases, has multi- factorial etiology. Can the Other Conditions of Elevated LH/hCG Lead to AD Development in Women? Short-term LH elevations, such as preovulatory surges, are not likely to lead to AD development, not only because of its Brain Ovaries AdrenalsPancreas Adipose Ɵssue LH LH Androgens AndrogensInilusn Estrogens LH Figure 1. The proposed model of luteinizing hormone (LH) involvement in the development of Alzheimer disease (AD) in elderly women. In this model, LH released from anterior pituitary gland gets back to hippocampus to promote amyloidogenic pathway of amyloid precursor protein (APP) metabolism (line thickness denotes the primary action). Secondarily, LH can also act on peripheral tissues either to increase androgens secretion or insulin release. The androgens are then aromatized into estrogens in adipose tissue, which positively feedback to release more LH. Endogenously produced brain LH may also have a role in the disease process, but this remains to be further investigated. Rao 5 by guest on July 20, 2016rsx.sagepub.comDownloaded from
  6. 6. shorter duration of elevation but also due to concomitant increase in estrogen levels, which are neuroprotective.19,68-70 Similarly, pregnancy may also not lead to the AD development, even though hCG levels are elevated for a longer duration, because estrogen levels are also elevated to a greater degree at the same time. These predictions should be further ver- ified by epidemiological studies on AD incidence in women who have incessantly ovulated, like nuns, as compared with those who had interrupted cycles due to pregnancy. Similar information can come from comparing women who had multiple pregnancies with those who had fewer pregnancies during their lifetime. The AD incidence in other elevated LH/hCG states, such as polycystic ovarian syndrome (PCOS) and pituitary and placental (gestational trophoblastic neoplasms) tumors that secrete exces- sive amounts of LH and hCG, respectively, in the absence of concomitant increase in estrogen levels, is unknown. However, there are leads for women with PCOS. There are reports on women with PCOS having long-term health consequences including cognitive decline and altered brain microstruc- ture.148-150 Furtheraffirmationcancome fromretrospectivechart reviews of the patients. The possibility of AD incidence in rare cases,suchasinactivating andactivating LH/hCGreceptormuta- tions, can also be obtained by the reviews of patient charts. Infants born from Down syndrome pregnancies seem to develop AD at younger ages.129-131 This is presumably due to intrauterine exposure to high maternal hCG levels. However, whether the same high hCG levels can influence AD develop- ment in the mother is not known. But it is not likely because of a concomitant elevation in estrogen levels in the mother. Potential Mechanisms of LH Actions in AD The following scenarios can be envisioned from what is already known about the LH/hCG actions in neurons, glial cells, and in the other somatic cells.27,30,33,34,36-40,42,48,50,51,55 The LH actions can be nongenomic and genomic. In both cases, initial cell surface receptor binding is required. The binding results in an activation of second messenger signaling systems such as cAMP/PKA, protein kinase C (PKC), MAPK, and so on. The second messengers can then mediate the nongenomic actions such as alterations in protein phosphorylation and ion flux changes. The phosphorylation may include secretases, other enzymes, proteins associated with APP metabolism toward the amyloidogenic pathway, hyperphosphorylation of abnormal tau proteins, and so on. The chronic actions may require genomic changes, where activated kinases, directly and indirectly, affect the transacting factors, which could either increase or decrease the transcrip- tion of genes. However, the identity of these genes is unknown for the most part. The LH actions may also include influencing the stability of preexisting transcripts, their translation efficiency, and post- translational modifications of proteins. These changes could involve both nongenomic and/or genomic mechanisms. In the above scenarios, the molecular details are not known. Obviously, a great deal of further research is required to fill the knowledge gaps to better understand how LH/hCG acts, which could reveal new therapeutic targets. Further Research to Answer Some Important Questions on AD in Elderly Women The AD development in elderly women is due to physiological hormonal changes that are associated with aging. Since not all women going through these changes will develop AD, others such as genetic, epigenetic, environmental, lifestyle factors, and so on, must also be required. The identity of them remains elusive, and only further research can reveal them. Even though AD is a terrible disease and deaths from it are increasing rela- tive to cancer and heart disease, AD research funding (US$660 millions) pales by comparison with cancer (US$5.4 billion) and heart disease (US$1.2 billion).151 This disparity must somehow be reconciled in order to make the necessary scientific advances to conquer AD. Part of the further research should focus on answering the following fundamental questions. a. Does age alter brain’s response to estrogens and LH? b. What role, if any, FSH plays in AD development? c. The brain can also make estrogens and LH.152-160 The question then are: 1. What role do the brain-derived hormones play in AD development in contrast to those that come from periphery? 2. Is there a relationship between peripheral and brain levels of estrogens and LH? 3. Do high estrogens suppress brain LH signaling dur- ing premenopausal period and that this suppression somehow is lost in an age-dependent manner dur- ing postmenopausal years? If so, why and how the suppression mechanisms are lost during aging. d. What molecular mechanisms are involved in the neuro- protective role of estrogens? e. Luteinizing hormone/hCG do not seem to be neurotoxic when estrogen levels are high. How does the falling estrogen levels trigger/enhance the development of neu- rotoxicity of LH? f. What are the critical genetic and nongenetic factors that work in concert with LH in AD development? g. Does LH regulate brain’s insulin synthesis as it does in the pancreas? Role of Testosterone (T) and LH in AD Development in Elderly Men Elderly men account for about one-third of total cases with AD.1,2 This gender difference could partly be due to a higher mortality from atherosclerosis, cardiovascular disease, and so 6 Reproductive Sciences by guest on July 20, 2016rsx.sagepub.comDownloaded from
  7. 7. on, among them, as compared with elderly women. The other reason could be hormonal changes. For example, age- dependent hormonal changes are different in elderly men as compared with elderly women. Thus, elderly men have gradual increase and lower peak LH levels as compared with elderly women.161-167 Moreover, the decrease in serum T levels is gradual as compared with faster and greater decrease in estro- gens in elderly women.161,163,164,166-168 It is also possible that the brain sensitivity to androgens is maintained in elderly men, whereas the estrogen sensitivity dramatically decreases in elderly women. Elderly men also have an increased androgen resistance and what role this might play is unknown.18 Inter- estingly, the gender difference is even seen in APP transgenic mice. Thus, male mice have a lower brain Ab deposition than female mice.169 It is possible that both decreasing T levels and increasing LH levels are involved in AD development in elderly men.18 However, it is not clear whether T is secondary to LH and vice versa or both work in concert in reciprocal manner.18,170-178 In support of the LH involvement, increase in its levels results in neuropathological and cognitive changes characteristic of AD, reducing its levels in male gonadectomized mice, causing cog- nitive benefits, and LH/hCG receptor variant reduces AD risk in men.18,171,175-179 The risk of death in men with AD decreases when they are placed on GnRHa therapy for prostate cancer.180 The GnRHa treatment works in elderly men, with variable results just as in elderly women with AD.18 Multiple lines of evidence suggest that T is neuroprotective and decrease in its levels leads to neuropathological and beha- vioral changes that are the hallmark of AD.20,181-183 The evi- dence includes: – Testosterone levels are positively associated with cogni- tion in elderly men.184 – The AD development increases as the T levels decline during aging.170 – The men with AD have a lower T levels, low T levels are an independent risk factor for AD, and T deprivation increases the future AD risk.99,112,184 – Testosterone levels are negatively associated and LH levels are positively associated with the brain Ab deposition during early stages (mild cognitive impair- ment) and presymptomatic phase of AD (subjective memory complemers).177 – The T therapy works in hypogonadal men with AD.185 – Men who have undergone chemical castration have increased Ab levels.171,186,187 – Men with AD have reduced brain T levels.188 – Declining T levels is a risk factor for AD.183,188,189 – Testosterone levels are inversely correlated with Ab levels.171,176,187 – Testosterone has distinct effects on plasma and cere- brospinal fluid levels of Ab protein.189,190 – Testosterone decreases neuronal Ab secretion.20,174 – Testosterone decreases Ab toxicity in cultured hippo- campal cells.18,191 – Testosterone improves neuronal viability, synaptic plasticity, cognition, and reduce AD pathology treatment.173,184,192,193 – Gonadectomy increases Ab levels, and reducing LH levels improves cognition.176,178 – Androgen depletion in transgenic mice increases brain Ab deposition and impairs hippocampal-dependent behavioral performance.175 – Testosterone regulates the development of AD neuro- pathology in mice model of AD.194,195 – T lowers Ab levels in a 3x Tg-D male mice.18 The studies on whether T conversion to E is necessary in AD are inconclusive.18,196 Regardless, the findings suggest that T replacement should work for the treatment of elderly men with AD. However, the results are contradictory, which is eerily similar to the results of HRT or ERT in women with AD.18 If both T decline and LH rise are independently involved in AD development, perhaps a better approach will be to combine T replacement with GnRHa in the treatment of elderly men. This possibility requires clinical verification. Since T replacement therapy may increase prostate cancer and cardiovascular risks, it can be replaced with selective androgen receptor modulators.18,197 Currently Approved Treatments for AD There are 6 Food and Drug Administration (FDA)-approved prescription drugs for the treatment of AD symptoms.198 Four are acetylcholinesterase inhibitors and they are sold under brand names of Aricept, Razadyne, Exelon, and Cognex.198 The first 3 are commonly prescribed, and Cognex is rarely prescribed because of the side effects, including liver dam- age.198 They all work by increasing acetylcholine, a neuro- transmitter required for memory, judgment, and thought processes.198 The fifth is Namenda (brand name), which blocks N-methyl-D-aspartate (NMDA) receptors, thus protect neurons from an excess glutamate.198 The sixth one Namzaric, a com- bination of Aricept and Namenda (brand name Namzaric), is indicated for patients with moderate to severe disease.198 Acet- ylcholinesterase inhibitors are indicated either for all stages (Aricept) or only for those with mild to moderate disease (Razadyne and Exelon). All the drugs are rather well tolerated. They cannot, however, reverse the disease or stop further destruction of the nerve cells. Thus, their effectiveness decreases as the nerve cell damage increases.198 Finally, there is an antiepileptic drug, Levetiracetam, which has been tested in patients with dementia at 12 times the lower dose than that used in epileptics.199 It works by decreasing the hippocampal neuronal overactivity.199,200 The FDA has recently approved it for phase III clinical trials.199 There are several new drugs in pipeline that decrease the Ab production, inhibit its aggregation, or increase its clearance.201 They are MK-8931, which block the b-secretase activity,198 and Solanezumab, a monoclonal antibody, which binds Ab, Rao 7 by guest on July 20, 2016rsx.sagepub.comDownloaded from
  8. 8. prevent the formation of new plaques and carry excess Ab away from the brain.198 Abnormal form of tau protein can collapse and twist into tangles, which destroy microtubules and ultimately neu- rons.14,16 AADvac1 is a vaccine that stimulates the body’s immune system to attack an abnormal tau protein.198 Microglia act as a first line of immune defense in the brain and it helps clear Ab from the brain. CSP-1103, a microglial modulator, is being evaluated for AD therapy. Insulin is required for brain health.6,202,203 Part of the brain insulin is locally synthesized, and the rest comes from periph- eral circulation.203-206 Insulin activates its brain receptors to regulate hippocampal metabolism, memory formation, and so on.203,207 In type 2 diabetes, hippocampal Ab accumulation increases, and this increase prevents insulin binding to its receptors, resulting in insulin resistance and exacerbation of neurodegeneration.202,203,205 Therefore, nasal insulin adminis- tration is being evaluated to increase brain insulin signaling.198 Future Therapeutic Possibilities The involvement of LH in AD development in postmenopausal women offers an obvious therapeutic approach of reducing its levels by treatment with GnRHa. There are several studies demonstrating the therapeutic benefit of GnRHa treatment.208 However, a recent phase 2 48-week, double-blind, and placebo- controlled clinical study on 109 women aged 65 years or older, with mild to moderate AD, with low- or high-dose GnRHa (Lupron), showed no benefit especially with a low dose.209 The high dose, on the other hand, showed statistically nonsignifi- cant trend of benefit.209 The individuals in the high-dose group, who are already taking acetylcholinesterase inhibitor, showed a statistically significant improvement.209 This is likely to be due to the differences in their mechanism of action. More such combination therapies and with varying doses need to be tested to determine whether therapeutic efficiency can be further improved. The failure of Lupron treatment alone is not the last verdict, because most of the other previous clinical trials of AD drugs on people with dementia diagnosis have failed, presumably due to prior irreversible brain damage, small sample size, and host of other factors such as dose, route, duration of treatment, and so on. Since the treatment failures are common, one should consider starting the therapies on individuals who have a strong family history and/or at high risk, as determined by PET, spinal taps, or brain scans, or even at the onset of early warning signs such as memory loss, confusion, frequent falling, disorienta- tion, inability to comprehend, and complete the simple tasks. The other therapeutic possibilities include developing even more potent GnRHa, LH/hCG receptor inhibitors, and LH/hCG receptor gene silencers that can be selectively directed to hip- pocampus and frontal cortex. Multipronged therapeutic approaches that prevent further destruction of nerve cells and also reverse pathological biochemical changes will be optimal to combat AD. It is estimated that any therapy that can delay AD progression even by 5 years could reduce the disease prevalence by 40% and saves over US$300 billion for the US economy.199 Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no financial support for the research, author- ship, and/or publication of this article. References 1. Alzheimer’s Society. What is Alzheimer’s disease? 2014. Web site. www.alzheimers.org.uk/site/scripts/documents_info.php? documentID¼100. Accessed October 3, 2015. 2. Center for Disease Control and Prevention. Alzheimer’s disease. 2015. Web site. http://www.cdc.gov/aging/aginginfo/alzheimers .htm. Updated March 5, 2015. Accessed October 3, 2015. 3. 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