The gonadotropin connection in Alzheimer’s disease

Although not traditionally thought of as regulators of neuronal function, the hypothalamic-pituitary-gonadal (HPG) hormones luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), and activins possess neuronal receptors. These receptors are found throughout the limbic system on a number of different cell types, and, like reproductive tissues, the expression of these receptors is regulated by hormonal feedback loops. These hormones and their receptors regulate structure and a diverse range of functions in the brain. Therefore, it is not surprising that the dysregulation of the HPG axis with menopause and andropause (leading to elevated LH, GnRH, and activin signaling but decreased sex steroid signaling) might promote alterations in both the structure and function of neuronal cells. To date, most evidence has accumulated for a role of LH in promoting neurodegenerative changes. LH is known to cross the blood-brain barrier, receptors for LH are most concentrated in the hippocampus, that region of the brain most vulnerable to Alzheimer’s disease (AD) and LH is significantly elevated in both the serum and the pyramidal neurons of AD subjects. LH promotes the amyloidogenic processing of the amyloid-β precursor protein in vitro, and the antigonadotropin leuprolide acetate decreases amyloid generation in mice. Moreover, leuprolide acetate improves the cognitive performance and decreases amyloid-β deposition in aged transgenic mice carrying the Swedish AβPP mutation. Therefore, the elevation of LH with the dysregulation of the HPG axis at menopause and andropause is a physiologically relevant signal that could promote neurodegeneration. Epidemiological support for a role of LH/GnRH in AD is evidenced by a reduction in neurodegenerative disease among prostate cancer patients a group known to GnRH agonists. Clinical trials are underway for the treatment of AD using GnRH analogs and should provide further insights into the gonadotropin connection in AD.

[1]  D. Selkoe,et al.  Alzheimer's Disease--Genotypes, Phenotype, and Treatments , 1997, Science.

[2]  Kristina Hotakainen,et al.  Human chorionic gonadotropin in cancer. , 2004, Clinical biochemistry.

[3]  Atkinson,et al.  An Association of Elevated Serum Gonadotropin Concentrations and Alzheimer Disease? , 2000, Journal of neuroendocrinology.

[4]  Sumire V. Kobayashi,et al.  Association of Tau Protein with Microtubules in Living Cells , 1986, Annals of the New York Academy of Sciences.

[5]  S. Wasser,et al.  Noninvasive reproductive steroid hormone estimates from fecal samples of captive female sea otters (Enhydra lutris). , 2003, General and comparative endocrinology.

[6]  W. Crowley,et al.  Perifusion of rat pituitary cells with gonadotropin-releasing hormone, activin, and inhibin reveals distinct effects on gonadotropin gene expression and secretion. , 1993, Endocrinology.

[7]  A. Hsueh,et al.  Cystine Knot of the Gonadotropin α Subunit Is Critical for Intracellular Behavior but Not for in Vitro Biological Activity* , 1997, The Journal of Biological Chemistry.

[8]  A. Korten,et al.  The prevalence of dementia: A quantitative integration of the literature , 1987, Acta psychiatrica Scandinavica.

[9]  J. Buckwalter,et al.  Estrogen replacement therapy in older women. Comparisons between Alzheimer's disease cases and nondemented control subjects. , 1994, Archives of neurology.

[10]  P. Timiras,et al.  Estrogens influence growth, maturation, and amyloid beta-peptide production in neuroblastoma cells and in a beta-APP transfected kidney 293 cell line. , 1997, Advances in experimental medicine and biology.

[11]  M. Tokuda,et al.  Copyright � American Society of Andrology Effects of Luteinizing Hormone, Follicle-Stimulating Hormone, and Epidermal Growth Factor on Expression and Kinase Activity of Cyclin-Dependent Kinase 5 in Leydig , 2022 .

[12]  M. Shelanski,et al.  Neurogenic Effect of β-Amyloid Peptide in the Development of Neural Stem Cells , 2004, The Journal of Neuroscience.

[13]  A. Garvin,et al.  Inhibition of insulin like growth factor II autocrine growth of Wilms' tumor by suramin in vitro and in vivo. , 1996, Cancer letters.

[14]  C. Atwood,et al.  Living and Dying for Sex , 2004, Gerontology.

[15]  L. Ewing,et al.  Effects of hypophysectomy and alterations in spermatogenic function on Leydig cell volume, number, and proliferation in adult rats. , 1990, Journal of andrology.

[16]  J. Morrison,et al.  Estrogen and Aging Affect the Subcellular Distribution of Estrogen Receptor-α in the Hippocampus of Female Rats , 2002, The Journal of Neuroscience.

[17]  S. Gandy,et al.  Ovariectomy and 17β-estradiol modulate the levels of Alzheimer's amyloid β peptides in brain , 2000, Experimental Gerontology.

[18]  S. Papasozomenos,et al.  Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  F. Watt,et al.  beta-catenin signalling modulates proliferative potential of human epidermal keratinocytes independently of intercellular adhesion. , 1999, Development.

[20]  R. Neve,et al.  beta-Secretase cleavage of the amyloid precursor protein mediates neuronal apoptosis caused by familial Alzheimer's disease mutations. , 2001, Brain research. Molecular brain research.

[21]  U. Gärtner,et al.  Expression of the cyclin‐dependent kinase inhibitor p16 in Alzheimer's disease , 1996, Neuroreport.

[22]  J. Heath,et al.  Down-regulation of WW Domain-containing Oxidoreductase Induces Tau Phosphorylation in Vitro , 2004, Journal of Biological Chemistry.

[23]  T. Yoneda,et al.  Smad5 and DPC4 Are Key Molecules in Mediating BMP-2-induced Osteoblastic Differentiation of the Pluripotent Mesenchymal Precursor Cell Line C2C12* , 1998, The Journal of Biological Chemistry.

[24]  W. Utian.  Effect of postmenopausal estrogen therapy on diastolic blood pressure and bodyweight. , 1978, Maturitas.

[25]  B. Tycko,et al.  Earlier onset of Alzheimer's disease in men with Down syndrome , 1998, Neurology.

[26]  K. Thomas,et al.  Rate of disappearance in plasma of synthetic LH-RH intravenously injected in man. , 1978, Gynecologic and obstetric investigation.

[27]  K. Neve,et al.  DNA Synthesis and Neuronal Apoptosis Caused by Familial Alzheimer Disease Mutants of the Amyloid Precursor Protein Are Mediated by the p21 Activated Kinase PAK3 , 2003, The Journal of Neuroscience.

[28]  F. S. French,et al.  Immunohistochemical localization of the androgen receptor in rat and human tissues. , 1990, Endocrinology.

[29]  I. Kourides,et al.  Expression of Chorionic Gonadotropin α- and β-Genes in Normal and Neoplastic Human Tissues: Relationship to Deoxyribonucleic Acid Structure* , 1985 .

[30]  C. Jordan,et al.  Sex Differences, Laterality, and Hormonal Regulation of Androgen Receptor Immunoreactivity in Rat Hippocampus , 2002, Hormones and Behavior.

[31]  K. Grzeschik,et al.  The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor , 1987, Nature.

[32]  B. Winblad,et al.  Very Old Women at Highest Risk of Dementia and Alzheimer's Disease , 1997, Neurology.

[33]  Xiongwei Zhu,et al.  Activation of oncogenic pathways in degenerating neurons in Alzheimer disease , 2000, International Journal of Developmental Neuroscience.

[34]  C. Rao,et al.  Neurons from fetal rat brains contain functional luteinizing hormone/chorionic gonadotropin receptors. , 1997, Biology of reproduction.

[35]  P. Greengard,et al.  Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Estus,et al.  Production of the Alzheimer amyloid beta protein by normal proteolytic processing. , 1992, Science.

[37]  D. Jordan,et al.  Characterization and distribution of receptors for gonadotropin-releasing hormone in the rat hippocampus. , 1988, Neuroendocrinology.

[38]  H. Wiśniewski,et al.  Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[39]  R. Scott,et al.  Processing of the beta-amyloid precursor. Multiple proteases generate and degrade potentially amyloidogenic fragments. , 1993, The Journal of biological chemistry.

[40]  P. Greengard,et al.  Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. , 1994, The Journal of biological chemistry.

[41]  J. Shioi,et al.  Overexpression in Neurons of Human Presenilin-1 or a Presenilin-1 Familial Alzheimer Disease Mutant Does Not Enhance Apoptosis , 1998, The Journal of Neuroscience.

[42]  W. Klein,et al.  Microtubule-Associated Protein Tau Is Hyperphosphorylated during Mitosis in the Human Neuroblastoma Cell Line SH-SY5Y , 1994, Experimental Neurology.

[43]  I. Grundke‐Iqbal,et al.  Tau pathology in Alzheimer disease and other tauopathies. , 2005, Biochimica et biophysica acta.

[44]  D. Kirschner,et al.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. , 1990, Science.

[45]  M. Hirose,et al.  Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation. , 2004, Toxicology.

[46]  D. Selkoe,et al.  Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production , 1992, Nature.

[47]  C Oliver,et al.  Down's Syndrome and Alzheimer's disease: a review , 1986, Psychological Medicine.

[48]  T. Nikaido,et al.  HCG promotes proliferation of uterine leiomyomal cells more strongly than that of myometrial smooth muscle cells in vitro. , 2000, Molecular human reproduction.

[49]  C. Rao,et al.  Peripheral and Intracerebroventricular Administration of Human Chorionic Gonadotropin Alters Several Hippocampus-Associated Behaviors in Cycling Female Rats , 1995, Hormones and Behavior.

[50]  R. Mayeux,et al.  Endogenous estrogen levels and Alzheimer’s disease among postmenopausal women , 2000, Neurology.

[51]  B. Marchetti,et al.  Changes in hippocampal LH-RH receptor density during maturation and aging in the rat. , 1989, Brain research. Developmental brain research.

[52]  E. Rimon,et al.  Gonadotrophin-induced gene regulation in human granulosa cells obtained from IVF patients. Modulation of steroidogenic genes, cytoskeletal genes and genes coding for apoptotic signalling and protein kinases. , 2004, Molecular human reproduction.

[53]  G. Lindwall,et al.  Phosphorylation affects the ability of tau protein to promote microtubule assembly. , 1984, The Journal of biological chemistry.

[54]  G. Glenner,et al.  Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein , 1984 .

[55]  S. Papasozomenos,et al.  The heat shock-induced hyperphosphorylation of tau is estrogen-independent and prevented by androgens: implications for Alzheimer disease. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[56]  E. Hogervorst,et al.  The Controversy Over Levels of Sex Steroids in Cases with Alzheimer's Disease , 2004, Journal of neuroendocrinology.

[57]  C. Cotman,et al.  β-Amyloid protein promotes neuritic branching in hippocampal cultures , 1990, Neuroscience Letters.

[58]  H. Rubinfeld,et al.  The ERK cascade as a prototype of MAPK signaling pathways. , 2004, Methods in molecular biology.

[59]  Mark A. Smith,et al.  Dysregulation of the Hypothalamic-Pituitary-Gonadal Axis with Menopause and Andropause Promotes Neurodegenerative Senescence , 2005, Journal of neuropathology and experimental neurology.

[60]  TPA enhances growth hormone (GH) secretion effect of GH-releasing hormone (GHRH) by human gsp-positive pituitary somatotrophinomas , 2008, Journal of Tongji Medical University.

[61]  L. Bilezikjian,et al.  Erratum to “Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan-glycan” [Mol. Cell. Endocrinol. 180 (2001) 47–53] , 2002, Molecular and Cellular Endocrinology.

[62]  R. Martins,et al.  The role of beta amyloid in Alzheimer's disease: still a cause of everything or the only one who got caught? , 2004, Pharmacological research.

[63]  Mark A. Smith,et al.  Estrogen Replacement and Risk of Alzheimer Disease [1] (multiple letters) , 2003 .

[64]  D. C. Harris,et al.  Crystal structure of human chorionic gonadotropin , 1994, Nature.

[65]  H. Minaguchi,et al.  Effects of glucose and related substrates on the recovery of the electrical activity of gonadotropin-releasing hormone pulse generator which is decreased by insulin-induced hypoglycemia in the estrogen-primed ovariectomized rat , 1999, Brain Research.

[66]  H. Wiśniewski,et al.  Alzheimer paired helical filaments: Bulk isolation, solubility, and protein composition , 2004, Acta Neuropathologica.

[67]  H. Ostergaard,et al.  Immobilized antibodies to CD45 induce rapid morphologic changes and increased tyrosine phosphorylation of p56lck-associated proteins in T cells. , 1995, Journal of immunology.

[68]  B. Winblad,et al.  Alzheimer's disease : advances in etiology, pathogenesis, and therapeutics , 2001 .

[69]  S. Papasozomenos.  Heat Shock Induces Rapid Dephosphorylation of τ in Both Female and Male Rats Followed by Hyperphosphorylation Only in Female Rats: Implications for Alzheimer's Disease , 1996, Journal of neurochemistry.

[70]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[71]  H. Gutfreund.  I was lucky, I was there at the right time , 2003, Cellular and Molecular Life Sciences CMLS.

[72]  R. Brookmeyer,et al.  A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease , 1997, Neurology.

[73]  A. Gore,et al.  Menopausal increases in pulsatile gonadotropin-releasing hormone release in a nonhuman primate (Macaca mulatta). , 2004, Endocrinology.

[74]  R. Terry,et al.  ULTRASTRUCTURAL STUDIES IN ALZHEIMER'S PRESENILE DEMENTIA. , 1964, The American journal of pathology.

[75]  J. Nadeau,et al.  Luteinizing hormone induction of ovarian tumors: oligogenic differences between mouse strains dictates tumor disposition. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[76]  M. Esiri,et al.  Apoptosis-Related Protein Expression in the Hippocampus in Alzheimer’s Disease , 1997, Neurobiology of Aging.

[77]  M. Hunzicker-Dunn,et al.  Signal Transduction Pathways Activated by Chorionic Gonadotropin in the Primate Endometrial Epithelial Cells1 , 2003, Biology of reproduction.

[78]  E. Ravussin,et al.  Pennington Scientific Symposium on Mechanisms and Retardation of Aging , 2003, Experimental Gerontology.

[79]  S. Heck,et al.  Estrogen induces a rapid secretion of amyloid beta precursor protein via the mitogen-activated protein kinase pathway. , 2001, European journal of biochemistry.

[80]  R. Juliano,et al.  Integrins Regulate the Linkage between Upstream and Downstream Events in G Protein-coupled Receptor Signaling to Mitogen-activated Protein Kinase* , 2000, The Journal of Biological Chemistry.

[81]  R. Seger,et al.  Activation of MAPK Cascades by GnRH: ERK and Jun N-Terminal Kinase Are Involved in Basal and GnRH-Stimulated Activity of the Glycoprotein Hormone LHβ-Subunit Promoter. , 2002, Endocrinology.

[82]  S. Asthana,et al.  Estrogen and Cognition: A True Relationship? , 2004, Journal of the American Geriatrics Society.

[83]  A. Kastin,et al.  The half-life, metabolism and excretion of tritiated luteinizing hormone-releasing hormone (LH-RH) in man. , 1973, The Journal of clinical endocrinology and metabolism.

[84]  R. Neve,et al.  Alzheimer’s disease: a dysfunction of the amyloid precursor protein 1 1 Published on the World Wide Web on 11 September 2000. , 2000, Brain Research.

[85]  R. Martins,et al.  Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition* , 2004, Journal of Biological Chemistry.

[86]  R. Stouffer,et al.  The ovulatory gonadotrophin surge stimulates cyclooxygenase expression and prostaglandin production by the monkey follicle. , 2001, Molecular human reproduction.

[87]  Yaakov Stern,et al.  Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease , 1996, The Lancet.

[88]  J. Lafrancois,et al.  Modulation of Aβ peptides by estrogen in mouse models , 2002, Journal of neurochemistry.

[89]  C. Cotman,et al.  Amyloid beta protein enhances the survival of hippocampal neurons in vitro. , 1989, Science.

[90]  M. Memo,et al.  Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path? , 2001, Trends in Neurosciences.

[91]  M. Ciotti,et al.  Increased amyloidogenic secretion in cerebellar granule cells undergoing apoptosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[92]  F. Stam,et al.  Age incidence of senile brain amyloidosis. , 1986, Pathology, research and practice.

[93]  L. Johnson,et al.  Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. , 1984, The Journal of clinical endocrinology and metabolism.

[94]  S. Asthana,et al.  High-dose estradiol improves cognition for women with AD , 2001, Neurology.

[95]  M. Tabaton,et al.  Full length α-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects , 2000, Neuroscience Letters.

[96]  R. L. Moss.  Actions of hypothalamic-hypophysiotropic hormones on the brain. , 1979, Annual review of physiology.

[97]  R. Williams,et al.  Williams Textbook of endocrinology , 1985 .

[98]  K. Marder,et al.  Cognitive function in nondemented older women who took estrogen after menopause , 1998, Neurology.

[99]  Y. Zeng,et al.  EGFR tyrosine kinase inhibitor AG1478 inhibits cell proliferation and arrests cell cycle in nasopharyngeal carcinoma cells. , 2001, Cancer letters.

[100]  D. Rubinow,et al.  Basal and stimulated gonadotropin levels in the perimenopause. , 1996, American journal of obstetrics and gynecology.

[101]  I. Huhtaniemi,et al.  Oestrogen-dependent expression of LH/hCG receptors in pig Fallopian tube and their role in relaxation of the oviduct. , 1999, Journal of reproduction and fertility.

[102]  George Perry,et al.  The Role of Mitogen-Activated Protein Kinase Pathways in Alzheimer’s Disease , 2002, Neurosignals.

[103]  S. Yang,et al.  Activation of gonadotropin-releasing hormone receptors produces neuronal excitation in the rat hippocampus. , 1999, The Chinese journal of physiology.

[104]  T. Tabira,et al.  Developmental and aging changes in the expression patterns of beta-amyloid in the brains of normal and down syndrome cases , 1990, Brain and Development.

[105]  J. Carvalheira,et al.  Novel signal transduction pathway for luteinizing hormone and its interaction with insulin: activation of Janus kinase/signal transducer and activator of transcription and phosphoinositol 3-kinase/Akt pathways. , 2003, Endocrinology.

[106]  Takashi Isobe,et al.  Expression of α and β genes of human chorionic gonadotropin in lung cancer , 1997 .

[107]  A. Mason,et al.  Activin stimulates secretion of follicle-stimulating hormone from pituitary cells desensitized to gonadotropin-releasing hormone. , 1988, Biochemical and biophysical research communications.

[108]  Robert B. Petersen,et al.  Mitochondrial abnormalities in Alzheimer disease , 2000, Neurobiology of Aging.

[109]  T. Hämäläinen,et al.  Ontogeny of luteinizing hormone receptor gene expression in the rat testis. , 1994, Endocrinology.

[110]  A. Krichevsky,et al.  Immunological detection of membrane-associated human luteinizing hormone correlates with gene expression in cultured human cancer and fetal cells. , 1995, Endocrinology.

[111]  P. Greengard,et al.  Estrogen reduces neuronal generation of Alzheimer β-amyloid peptides , 1998, Nature Medicine.

[112]  R Brookmeyer,et al.  Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. , 1998, American journal of public health.

[113]  G. Ehret,et al.  Estrogen-receptor occurrence in the female mouse brain: Effects of maternal experience, ovariectomy, estrogen and anosmia , 1994, Journal of Physiology-Paris.

[114]  I. Konishi,et al.  Review: Gonadotropins and Development of Ovarian Cancer , 1999, Oncology.

[115]  R. L. Moss,et al.  Midbrain central gray: LHRH infusion enhances lordotic behavior in estrogen-primed ovariectomized rats , 1979, Brain Research Bulletin.

[116]  A. Matsuno,et al.  Modulation of Protein Kinases and Microtubule-associated Proteins and Changes in Ultrastructure in Female Rat Pituitary Cells: Effects of Estrogen and Bromocriptine , 1997, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[117]  C. Arias,et al.  Estradiol and progesterone modify microtubule associated protein 2 content in the rat hippocampus , 2002, Brain Research Bulletin.

[118]  R. Martins,et al.  Amyloid‐β‐induced toxicity of primary neurons is dependent upon differentiation‐associated increases in tau and cyclin‐dependent kinase 5 expression , 2003, Journal of neurochemistry.

[119]  J. Trojanowski,et al.  The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[120]  Donald P. McDonnell,et al.  Hormone Therapy: Physiological Complexity Belies Therapeutic Simplicity , 2004, Science.

[121]  B. Ponder,et al.  Administration of gonadotropins stimulates proliferation of normal mouse ovarian surface epithelium. , 1999, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[122]  M. Lerman,et al.  Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. , 1987, Science.

[123]  L. Whalley,et al.  Epidemiology of Alzheimer's presenile dementia in Scotland, 1974-88. , 1993, BMJ.

[124]  E. Rimon,et al.  Gonadotropin-induced gene regulation in human granulosa cells obtained from IVF patients: modulation of genes coding for growth factors and their receptors and genes involved in cancer and other diseases. , 2004, International journal of oncology.

[125]  G. Casadesus,et al.  Gonadotropins and Alzheimer's disease: the link between estrogen replacement therapy and neuroprotection. , 2004, Acta neurobiologiae experimentalis.

[126]  B. Marchetti,et al.  Modulation of hippocampal LHRH receptors by sex steroids in the rat , 1988, Peptides.

[127]  George Perry,et al.  Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer's disease pathology , 2002, Journal of neuroscience research.

[128]  S. Takeda,et al.  Expression of V642 APP mutant causes cellular apoptosis as Alzheimer trait‐linked phenotype. , 1996, The EMBO journal.

[129]  J. Brion,et al.  Distribution of the phosphorylated microtubule-associated protein tau in developing cortical neurons , 1994, Neuroscience.

[130]  J. Ávila,et al.  Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3, and beta-catenin in the hippocampus , 2004, Molecular and Cellular Neuroscience.

[131]  J. Marshall,et al.  Ovarian regulation of pituitary inhibin subunit and activin receptor type II gene expression: evidence for a nonsteroidal inhibitory substance. , 1994, Endocrinology.

[132]  Androgens, andropause and neurodegeneration: exploring the link between steroidogenesis, androgens and Alzheimer's disease. , 2005, Cellular and molecular life sciences : CMLS.

[133]  R. Tanzi,et al.  Role of free radicals and metal ions in the pathogenesis of Alzheimer's disease. , 1999, Metal ions in biological systems.

[134]  E. Bullmore,et al.  Society for Neuroscience Abstracts , 1997 .

[135]  P. Licht,et al.  Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain. , 1993, Endocrinology.

[136]  B. Doble,et al.  Selective monoclonal antibody recognition and cellular localization of an unphosphorylated form of connexin43. , 1997, Experimental cell research.

[137]  A. Nunomura,et al.  Oxidative Damage Is the Earliest Event in Alzheimer Disease , 2001, Journal of neuropathology and experimental neurology.

[138]  Alejandra del C. Alonso,et al.  Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules , 1996, Nature Medicine.

[139]  M. Kirschner,et al.  Tau protein function in living cells , 1986, The Journal of cell biology.

[140]  J. S. Foster,et al.  Activation of mitogen-activated protein kinases by gonadotropins and cyclic adenosine 5'-monophosphates in porcine granulosa cells. , 1996, Biology of reproduction.

[141]  D. Weiner,et al.  Subset-specific effects of sex hormones and pituitary gonadotropins on human lymphocyte proliferation in vitro. , 1993, Clinical immunology and immunopathology.

[142]  G. Rutter,et al.  Overexpression of lactate dehydrogenase A attenuates glucose‐induced insulin secretion in stable MIN‐6 β‐cell lines , 1998, FEBS letters.

[143]  S. D. Murphy,et al.  In vitro and in vivo modulation of cholinergic muscarinic receptors in rat lymphocytes and brain by cholinergic agents. , 1990, International journal of immunopharmacology.

[144]  R. Webber,et al.  In vitro culture of rabbit growth plate chondrocytes. 1. Age-dependence of response to fibroblast growth factor and "chondrocyte growth factor". , 1981, Growth.

[145]  W. Malarkey,et al.  Human thymocytes secrete luteinizing hormone: an autocrine regulator of T-cell proliferation. , 1992, Biochemical and biophysical research communications.

[146]  D. Pfaff,et al.  Excitability of female rat central gray cells with medullary projections: changes produced by hypothalamic stimulation and estrogen treatment. , 1980, Journal of neurophysiology.

[147]  David M. A. Mann,et al.  The pathological association between down syndrome and Alzheimer disease , 1988, Mechanisms of Ageing and Development.

[148]  S. Vasan,et al.  A preliminary study on the possible role for luteinizing hormone in androgen independent growth of prostate. , 2001, Reproductive biomedicine online.

[149]  P. Mellon,et al.  Activin A Regulation of Gonadotropin-Releasing Hormone Synthesis and Release in vitro , 1999, Neuroendocrinology.

[150]  K. Titani,et al.  Fetal‐Type Phosphorylation of the τ in Paired Helical Filaments , 1992 .