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Folia Neuropathologica
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vol. 56
Original paper

Human chorionic gonadotropin decreases the phosphorylated tau protein level in streptozotocin-Alzheimeric male rats’ hippocampus

Gozal Bahlakeh, Mehrdad Jahanshahi, Mohsen Saeidi

Folia Neuropathol 2018; 56 (2): 141-150
Online publish date: 2018/06/28
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The pharmacological suppression of luteinising hormone or human chorionic gonadotropin (hCG) can reduce Aβ plaques in the brains of rats and mice, but the effects of hCG on the phosphorylated tau protein level in the hippocampus have not been studied. Therefore, we investigated the effects of hCG on the phosphorylated tau protein level and its effect on hCG receptor-immunoreactive neuron density in the hippocampus of Alzheimer’s disease (AD) model rats (streptozotocin [STZ] injected intracerebroventricularly).

Material and methods
The rats were administered hCG (50, 100, and 200 IU/200 µl saline, intraperitoneally) or vehicle once/day for three days after injection of STZ. The passive avoidance memory test was performed 6 hours after the last hCG injection. The phosphorylated tau protein level in the hippocampus was measured by ELISA, and hCG receptor-immunoreactive neurons were shown by immunohistochemical technique in areas of hippocampus.

Treatment with hCG attenuated memory deficiencies and reduced the level of phosphorylated tau protein in the hippocampus. hCG also improved the density of hCG receptor-immunoreactive neurons. The high dose of hCG hormone (200 IU/200 µl saline) seemed to have a significant effect on passive avoidance memory, phosphorylated tau protein concentration, and accumulation of hCG receptor-immunoreactive neurons in Alzheimeric rats’ hippocampus.

In conclusion, hCG can provide protection against memory deficits induced by STZ and it can inhibit accumulation of tau hyperphosphorylation in the hippocampus. Furthermore, hCG can increase the hCG receptor-ir neurons number in the rats hippocampus after ICV injection of STZ.


hCG, streptozotocin, passive avoidance memory, phosphorylated tau protein, hCG receptor, hippocampus

Agrawal R, Tyagi E, Shukla R, Nath C. A study of brain insulin receptors, AChE activity and oxidative stress in rat model of ICV STZ induced dementia. Neuropharmacology 2009; 56: 779-787.
Agrawal R, Tyagi E, Shukla R, Nath C. Insulin receptor signaling in rat hippocampus: a study in STZ (ICV) induced memory deficit model. Eur Neuropsychopharm 2011; 21: 261-273.
Al-Hader AA, Lei ZM, Rao CV. Neurons from fetal rat brains contain functional luteinizing hormone/chorionic gonadotropin receptors. Biol Reprod 1997; 56: 1071-1076.
Al-Hader AA, Lei ZM, Rao CV. Novel expression of functional luteinizing hormone/chorionic gonadotropin receptors in cultured glial cells from neonatal rat brains. Biol Reprod 1997; 56: 501-507.
Anastasio TJ. Data-driven modeling of Alzheimer Disease pathogenesis. J Theor Biol 2011; 290: 60-72.
Alzheimer’s Association. 2014 Alzheimer’s disease facts and figures. Alzheimers Dement 2014; 10: e47-e92.
Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12: 459-509.
Avila J. Tau phosphorylation and aggregation in Alzheimer’s disease pathology. FEBS Lett 2006; 580: 2922-2927.
Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau protein in both physiological and pathological conditions. Physiol Rev 2004; 84: 361-384.
Azami NS, Piri M, Oryan S, Jahanshahi M, Babapour V, Zarrin­dast MR. Involvement of dorsal hippocampal -adrenergic receptors in the effect of scopolamine on memory retrieval in inhibitory avoidance task. Neurobiol Learn Mem 2010; 93: 455-462.
Babahajian A, Fotovat N, Soleimani M. P17: HCG and Trolox Reduced the Apoptotic Hippocampus Neuronal Cells in Ischemia Reperfusion Mice Model. Shefaye Khatam 2015; 2: 67.
Babahajian A, Rasouli H, Katebi M, Sarveazad A, Soleimani M, Nobakht M. Effect of human chorionic gonadotropin and vitamine E on cellular density of CA1 hippocampal area, learning ability and memory, following ischemia-reperfusion injury in mice. J Gorgan Uni Med Sci 2014; 15: Pe23-Pe27.
Barron AM, Verdile G, Taddei K, Bates KA, Martins RN. Effect of Chronic hCG administration on Alzheimer’s-related cognition and Aβ accumulation in PS1KI mice. Endocrinology 2010; 151: 5380-5388.
Berry A, Tomidokoro Y, Ghiso J, Thornton J. Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-β levels in female rats. Horm Behav 2008; 54: 143-152.
Bowen RL, Isley JP, Atkinson RL. An association of elevated serum gonadotropin concentrations and Alzheimer disease? J Neuroendocrinol 2000; 12: 351-354.
Bowen RL, Smith MA, Harris PL, Kubat Z, Martins RN, Castellani RJ, Perry G, Atwood CS. Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer’s disease pathology. J Neurosci Res 2002; 70: 514-518.
Bowen RL, Verdile G, Liu T, Parlow AF, Perry G, Smith MA, Martins RN, Atwood CS. Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-β precursor protein and amyloid-β deposition. J Biol Chem 2004; 279: 20539-20545.
Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 1995; 16: 271-278.
Brett M, Baxendale S. Motherhood and memory: a review. Psychoneuroendocrinology 2001; 26: 339-362.
Brunden KR, Ballatore C, Crowe A, Smith AB, Lee VM-Y, Trojanowski JQ. Tau-directed drug discovery for Alzheimer’s disease and related tauopathies: a focus on tau assembly inhibitors. Exp Neurol 2010; 223: 304-310.
Bukovsky A, Indrapichate K, Fujiwara H, Cekanova M, Ayala ME, Dominguez R, Caudle MR, Wimalsena J, Elder RF, Copas P, Foster JS, Fernando RI, Henley DC, Upadhyaya NB. Multiple luteinizing hormone receptor (LHR) protein variants, interspecies reactivity of anti-LHR mAb clone 3B5, subcellular localization of LHR in human placenta, pelvic floor and brain, and possible role for LHR in the development of abnormal pregnancy, pelvic floor disorders and Alzheimer’s disease. Reprod Biol Endocrinol 2003; 1: 46.
Bulic B, Pickhardt M, Mandelkow EM, Mandelkow E. Tau protein and tau aggregation inhibitors. Neuropharmacology 2010; 59: 276-289.
Burnham V, Sundby C, Laman-Maharg A, Thornton J. Luteinizing hormone acts at the hippocampus to dampen spatial memory. Horm Behav 2017; 89: 55-63.
Casadesus G, Webber KM, Atwood CS, Bowen RL, Perry G, Smith MA. P3-296: Luteinizing hormone mediates Alzheimer-type changes in neurons. Alzheimers Dement 2006; 2 Suppl: S462.
Casadesus G, Webber KM, Atwood CS, Pappolla MA, Perry G, Bowen RL, Smith MA. Luteinizing hormone modulates cognition and amyloid-β deposition in Alzheimer APP transgenic mice. BBA-Mol Basis Dis 2006; 1762: 447-452.
Chen Y, Liang Z, Blanchard J, Dai CL, Sun S, Lee MH, GrundkeIqbal I, Iqbal K, Liu F, Gong CX. A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: similarities to and differences from the transgenic model (3xTg-AD mouse). Mol Neurobiol 2013; 47: 711-725.
Correia SC, Santos RX, Santos MS, Casadesus G, Lamanna JC, Perry G, Smith MA, Moreira PI. Mitochondrial abnormalities in a streptozotocin-induced rat model of sporadic Alzheimer’s disease. Curr Alzheimer Res 2013; 10: 406-419.
Delacourte A, David JP, Sergeant N, Buee L, Wattez A, Vermersch P, Ghozali F, Fallet-Bianco C, Pasquier F, Lebert F, Petit H, Di Menza C. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology 1999; 52: 1158-1165.
Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX. Dysregulation of insulin signaling, glucose transporters, O-GlcNA­cylation, and phosphorylation of tau and neurofilaments in the brain: Implication for Alzheimer’s disease. Am J Pathol 2009; 175: 2089-2098.
Duyckaerts C, Hauw JJ. Diagnosis and staging of Alzheimer disease. Neurobiol Aging 1997; 18 (4 Suppl): S33-S42.
Goedert M, Jakes R, Crowther RA, Six J, Lübke U, Vandermeeren M, Cras P, Trojanowski JQ, Lee VM. The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci U S A 1993; 90: 5066-5070.
Grober E, Dickson D, Sliwinski MJ, Buschke H, Katz M, Crystal H, Lipton RB. Memory and mental status correlates of modified Braak staging. Neurobiol Aging 1999; 20: 573-579.
Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 2013; 80: 1778-1783.
Jahanshahi M, Nickmahzar E, Babakordi F. The effect of Ginkgo biloba extract on scopolamine-induced apoptosis in the hippocampus of rats. Anat Sci Int 2013; 88: 217-222.
Johnson GV, Stoothoff WH. Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 2004; 117: 5721-5729.
Kolarova M, García-Sierra F, Bartos A, Ricny J, Ripova D. Structure and pathology of tau protein in Alzheimer disease. Int
J Alzheimer Dis 2012; 2012: 731526.
Le Freche H, Brouillette J, Fernandez-Gomez FJ, Patin P, Caillierez R, Zommer N, Sergeant N, Buée-Scherrer V, Lebuffe G, Blum D, Buée L. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Anesthesiology 2012; 116: 779-787.
Lei ZM, Rao CV. Neural actions of luteinizing hormone and human chorionic gonadotropin. Semin Reprod Med 2001; 19: 103-109.
Lei ZM, Rao CV, Kornyei JL, Licht P, Hiatt ES. Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain. Endocrinology 1993; 132: 2262-2270.
Lin J, Li X, Yuan F, Lin L, Cook CL, Rao ChV, Lei Z. Genetic ablation of luteinizing hormone receptor improves the amyloid pathology in a mouse model of Alzheimer disease. J Neuropathol Exp Neurol 2010; 69: 253-261.
Liu P, Zou LB, Wang LH, Jiao Q, Chi TY, Ji XF, Jin G. Xanthoceraside attenuates tau hyperphosphorylation and cognitive deficits in intracerebroventricular-streptozotocin injected rats. Psychopharmacology 2014; 231: 345-356.
Liu T, Perry G, Chan – HW, Verdile G, Martins RN, Smith MA, Atwood CS. Amyloid-β-induced toxicity of primary neurons is dependent upon differentiation-associated increases in tau and cyclin-dependent kinase 5 expression. J Neurochem 2004; 88: 554-563.
Liu T, Wimalasena J, Bowen RL, Atwood CS. Luteinizing hormone receptor mediates neuronal pregnenolone production via up‐regulation of steroidogenic acute regulatory protein expression. J Neurochem 2007; 100: 1329-1339.
Lukács H. Rat as model for studying behavior effects of hCG. Semin Reprod Med 2001; 19: 111-119.
Lukacs H, Hiatt ES, Lei ZM, Rao CV. Peripheral and intracerebroventricular administration of human chorionic gonadotropin alters several hippocampus-associated behaviors in cycling female rats. Horm Behav 1995; 29: 42-58.
McFarland KC, Sprengel R, Phillips HS, Köhler M, Rosemblit N, Nikolics K, Segaloff DL, Seeburg PH. Lutropin-choriogonadotropin receptor: unusual member of the γ protein-coupled receptor family. Science 1989; 245: 494-499.
Meng XL, Rennert OM, Chan WY. Human chorionic gonadotropin induces neuronal differentiation of PC12 cells through activation of stably expressed lutropin/choriogonadotropin receptor. Endocrinology 2007; 148: 5865-5873.
Moghadami S, Jahanshahi M, Sepehri H, Amini H. Gonadectomy reduces the density of androgen receptor-immunoreactive neurons in male rat’s hippocampus: testosterone replacement compensates it. Behav Brain Funct 2016; 12: 5.
Niikura T, Hashimoto Y, Tajima H, Nishimoto I. Death and survival of neuronal cells exposed to Alzheimer’s insults. J Neurosci Res 2002; 70: 380-391.
Obulesu M, Lakshmi MJ. Apoptosis in Alzheimer’s disease: an understanding of the physiology, pathology and therapeutic avenues. Neurochem Res 2014; 39: 2301-2312.
Palm R, Chang J, Blair J, Garcia-Mesa Y, Lee HG, Castellani RJ, Smith MA, Zhu X, Casadesus G. Down-regulation of serum gonadotropins but not estrogen replacement improves cognition in aged-ovariectomized 3xTg AD female mice. J Neurochem 2014; 130: 115-125.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. Academic Press, San Diego 2007.
Rahman NA, Rao CV. Recent progress in luteinizing hormone/human chorionic gonadotrophin hormone research. Mol Hum Reprod 2009; 15: 703-711.
Rao C. Involvement of Luteinizing Hormone in Alzheimer Disease Development in Elderly Women. Reprod Sci 2016; 24: 355-368.
Rofe Y, Littner MB, Lewin I. Emotional experiences during the three trimesters of pregnancy. J Clin Psychol 1993; 49: 3-12.
Sasson R, Rimon E, Dantes A, Cohen T, Shinder V, Land-Bracha A, Amsterdam A. 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. Mol Hum Reprod 2004; 10: 299-311.
Shonesy BC, Thiruchelvam K, Parameshwaran K, Rahman EA, Karuppagounder SS, Huggins KW, Pinkert CA, Amin R, Dhana­sekaran M, Suppiramaniam V. Central insulin resistance and synaptic dysfunction in intracerebroventricular-streptozotocin injected rodents. Neurobiol Aging 2012; 33: 430. e435-430.
Short RA, O’Brien PC, Graff-Radford NR, Bowen RL. Elevated gonadotropin levels in patients with Alzheimer disease. Proc Mayo Clin Proc 2001; 76: 906-909.
Toth P, Lukacs H, Hiatt ES, Reid KH, Iyer V, Rao CV. Administration of human chorionic gonadotropin affects sleep-wake phases and other associated behaviors in cycling female rats. Brain Res 1994; 654: 181-190.
Van der Jeugd A, Ahmed T, Burnouf S, Belarbi K, Hamdame M, Grosjean ME, Humez S, Balschun D, Blum D, Buée L, D’Hooge R. Hippocampal tauopathy in tau transgenic mice coincides with impaired hippocampus-dependent learning and memory, and attenuated late-phase long-term depression of synaptic transmission. Neurobiol Learn Mem 2011; 95: 296-304.
Webber KM, Casadesus G, Atwood CS, Bowen RL, Perry G, Smith MA. Gonadotropins: a cohesive gender-based etiology of Alzheimer disease. Mol Cell Endocrinol 2007; 260: 271-275.
Weerateerangkull P, Praputpittaya C, Banjerdpongchai R. Effects of ascorbic acid on streptozotocin-induced oxidative stress and memory impairment in rats. Thai J Physiological Sci 2008; 20: 54-61.
Yang J, Pan P, Song W, Huang R, Li J, Chen K, Gong Q, Zhong J, Shi H, Shang H. Voxelwise meta-analysis of gray matter anomalies in Alzheimer’s disease and mild cognitive impairment using anatomic likelihood estimation. J Neurol Sci 2012; 316: 21-29.
Zamani Z, Reisi P, Alaei H, Pilehvarian A, Zamani Z. Effect of Royal Jelly (RJ) on Learning and Memory in Rats after Intracerebroventricular Injection of Streptozotocin (icv-STZ). J Isfahan Med Sch 2011; 28: 1825-1834.
Zhang W, Lei Z, Rao CV. Immortalized hippocampal cells contain functional luteinizing hormone/human chorionic gonadotropin receptors. Life Sci 1999; 65: 2083-2098.
Zhang Z, Simpkins JW. Okadaic acid induces tau phosphorylation in SH-SY5Y cells in an estrogen-preventable manner. Brain Res 2010; 1345: 176-181.
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