Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia
Abstract
:1. Introduction
2. Neurodegenerative Diseases
2.1. Parkinson’s Disease
2.2. Alzheimer’s Disease
2.3. Multiple Sclerosis
2.4. Amyotrophic Lateral Sclerosis
2.5. Huntington’s Disease
3. Sexual Dimorphism following Brain Ischemia
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Gillies, G.E.; Pienaar, I.S.; Vohra, S.; Qamhawi, Z. Sex Differences in Parkinson’s Disease. Front. Neuroendocr. 2014, 35, 370–384. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moser, V.A.; Pike, C.J. Obesity and Sex Interact in the Regulation of Alzheimer’s Disease. Neurosci. Biobehav. Rev. 2016, 67, 102–118. [Google Scholar] [CrossRef] [Green Version]
- Ramien, C.; Taenzer, A.; Lupu, A.; Heckmann, N.; Engler, J.B.; Patas, K.; Friese, M.A.; Gold, S.M. Sex Effects on Inflammatory and Neurodegenerative Processes in Multiple Sclerosis. Neurosci. Biobehav. Rev. 2016, 67, 137–146. [Google Scholar] [CrossRef] [PubMed]
- Gibson, C.L.; Attwood, L. The Impact of Gender on Stroke Pathology and Treatment. Neurosci. Biobehav. Rev. 2016, 67, 119–124. [Google Scholar] [CrossRef] [PubMed]
- Kipp, M.; Amor, S.; Krauth, R.; Beyer, C. Multiple Sclerosis: Neuroprotective Alliance of Estrogen–Progesterone and Gender. Front. Neuroendocrinol. 2012, 33, 1–16. [Google Scholar] [CrossRef] [PubMed]
- Li, R.; Singh, M. Sex Differences in Cognitive Impairment and Alzheimer’s Disease. Front. Neuroendocr. 2014, 35, 385–403. [Google Scholar] [CrossRef] [Green Version]
- Panzica, G.; Melcangi, R.C. Structural and Molecular Brain Sexual Differences: A Tool to Understand Sex Differences in Health and Disease. Neurosci. Biobehav. Rev. 2016, 67, 2–8. [Google Scholar] [CrossRef]
- Minati, L.; Edginton, T.; Bruzzone, M.G.; Giaccone, G. Current Concepts in Alzheimer’s Disease: A Multidisciplinary Review. Am. J. Alzheimers Dis. Other Demen. 2009, 24, 95–121. [Google Scholar] [CrossRef]
- Hirsch, L.; Jette, N.; Frolkis, A.; Steeves, T.; Pringsheim, T. The Incidence of Parkinson’s Disease: A Systematic Review and Meta-Analysis. Neuroepidemiology 2016, 46, 292–300. [Google Scholar] [CrossRef]
- Chaudhuri, K.R.; Healy, D.G.; Schapira, A.H.V. National Institute for Clinical Excellence Non-Motor Symptoms of Parkinson’s Disease: Diagnosis and Management. Lancet Neurol. 2006, 5, 235–245. [Google Scholar] [CrossRef]
- Mack, J.M.; Schamne, M.G.; Sampaio, T.B.; Pértile, R.A.N.; Fernandes, P.A.C.M.; Markus, R.P.; Prediger, R.D. Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms. Oxid. Med. Cell Longev. 2016, 2016, 3472032. [Google Scholar] [CrossRef] [Green Version]
- Gao, L.; Wu, T. The Study of Brain Functional Connectivity in Parkinson’s Disease. Transl. Neurodegener. 2016, 5, 18. [Google Scholar] [CrossRef] [Green Version]
- Sharma, N.; Nehru, B. Characterization of the Lipopolysaccharide Induced Model of Parkinson’s Disease: Role of Oxidative Stress and Neuroinflammation. Neurochem. Int. 2015, 87, 92–105. [Google Scholar] [CrossRef]
- Litim, N.; Morissette, M.; Di Paolo, T. Neuroactive Gonadal Drugs for Neuroprotection in Male and Female Models of Parkinson’s Disease. Neurosci. Biobehav. Rev. 2016, 67, 79–88. [Google Scholar] [CrossRef]
- Iwaki, H.; Blauwendraat, C.; Leonard, H.L.; Makarious, M.B.; Kim, J.J.; Liu, G.; Maple-Grødem, J.; Corvol, J.-C.; Pihlstrøm, L.; van Nimwegen, M.; et al. Differences in the Presentation and Progression of Parkinson’s Disease by Sex. Mov. Disord. 2021, 36, 106–117. [Google Scholar] [CrossRef]
- Martinez-Martin, P.; Falup Pecurariu, C.; Odin, P.; van Hilten, J.J.; Antonini, A.; Rojo-Abuin, J.M.; Borges, V.; Trenkwalder, C.; Aarsland, D.; Brooks, D.J.; et al. Gender-Related Differences in the Burden of Non-Motor Symptoms in Parkinson’s Disease. J. Neurol. 2012, 259, 1639–1647. [Google Scholar] [CrossRef]
- Haaxma, C.A.; Bloem, B.R.; Borm, G.F.; Oyen, W.J.G.; Leenders, K.L.; Eshuis, S.; Booij, J.; Dluzen, D.E.; Horstink, M.W.I.M. Gender Differences in Parkinson’s Disease. J. Neurol. Neurosurg. Psychiatry 2007, 78, 819–824. [Google Scholar] [CrossRef] [Green Version]
- Accolla, E.; Caputo, E.; Cogiamanian, F.; Tamma, F.; Mrakic-Sposta, S.; Marceglia, S.; Egidi, M.; Rampini, P.; Locatelli, M.; Priori, A. Gender Differences in Patients with Parkinson’s Disease Treated with Subthalamic Deep Brain Stimulation. Mov. Disord. 2007, 22, 1150–1156. [Google Scholar] [CrossRef]
- Miller, D.B.; Ali, S.F.; O’Callaghan, J.P.; Laws, S.C. The Impact of Gender and Estrogen on Striatal Dopaminergic Neurotoxicity. Ann. N. Y. Acad. Sci. 1998, 844, 153–165. [Google Scholar] [CrossRef]
- Dluzen, D.E.; McDermott, J.L.; Liu, B. Estrogen as a Neuroprotectant against MPTP-Induced Neurotoxicity in C57/B1 Mice. Neurotoxicol. Teratol. 1996, 18, 603–606. [Google Scholar] [CrossRef]
- Gillies, G.E.; Murray, H.E.; Dexter, D.; McArthur, S. Sex Dimorphisms in the Neuroprotective Effects of Estrogen in an Animal Model of Parkinson’s Disease. Pharm. Biochem. Behav. 2004, 78, 513–522. [Google Scholar] [CrossRef] [PubMed]
- Gillies, G.E.; McArthur, S. Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines. Pharm. Rev. 2010, 62, 155–198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mitra, S.; Chakrabarti, N.; Dutta, S.S.; Ray, S.; Bhattacharya, P.; Sinha, P.; Bhattacharyya, A. Gender-Specific Brain Regional Variation of Neurons, Endogenous Estrogen, Neuroinflammation and Glial Cells during Rotenone-Induced Mouse Model of Parkinson’s Disease. Neuroscience 2015, 292, 46–70. [Google Scholar] [CrossRef] [PubMed]
- Liu, B.; Dluzen, D.E. Oestrogen and Nigrostriatal Dopaminergic Neurodegeneration: Animal Models and Clinical Reports of Parkinson’s Disease. Clin. Exp. Pharm. Physiol. 2007, 34, 555–565. [Google Scholar] [CrossRef] [PubMed]
- Motta-Mena, N.V.; Puts, D.A. Endocrinology of Human Female Sexuality, Mating, and Reproductive Behavior. Horm. Behav. 2017, 91, 19–35. [Google Scholar] [CrossRef]
- Smith, K.M.; Dahodwala, N. Sex Differences in Parkinson’s Disease and Other Movement Disorders. Exp. Neurol. 2014, 259, 44–56. [Google Scholar] [CrossRef]
- Hirohata, M.; Ono, K.; Morinaga, A.; Ikeda, T.; Yamada, M. Anti-Aggregation and Fibril-Destabilizing Effects of Sex Hormones on Alpha-Synuclein Fibrils in Vitro. Exp. Neurol. 2009, 217, 434–439. [Google Scholar] [CrossRef]
- Thanky, N.R.; Son, J.H.; Herbison, A.E. Sex Differences in the Regulation of Tyrosine Hydroxylase Gene Transcription by Estrogen in the Locus Coeruleus of TH9-LacZ Transgenic Mice. Brain Res. Mol. Brain Res. 2002, 104, 220–226. [Google Scholar] [CrossRef]
- Jurado-Coronel, J.C.; Cabezas, R.; Ávila Rodríguez, M.F.; Echeverria, V.; García-Segura, L.M.; Barreto, G.E. Sex Differences in Parkinson’s Disease: Features on Clinical Symptoms, Treatment Outcome, Sexual Hormones and Genetics. Front. Neuroendocr. 2018, 50, 18–30. [Google Scholar] [CrossRef]
- Simpkins, J.W.; Yi, K.D.; Yang, S.-H.; Dykens, J.A. Mitochondrial Mechanisms of Estrogen Neuroprotection. Biochim. Biophys. Acta 2010, 1800, 1113–1120. [Google Scholar] [CrossRef]
- Wang, L.; Andersson, S.; Warner, M.; Gustafsson, J.-Å. Morphological Abnormalities in the Brains of Estrogen Receptor β Knockout Mice. Proc. Natl. Acad. Sci. USA 2001, 98, 2792–2796. [Google Scholar] [CrossRef] [Green Version]
- Campos, F.L.; Cristovão, A.C.; Rocha, S.M.; Fonseca, C.P.; Baltazar, G. GDNF Contributes to Oestrogen-Mediated Protection of Midbrain Dopaminergic Neurones. J. Neuroendocr. 2012, 24, 1386–1397. [Google Scholar] [CrossRef]
- Morale, M.C.; Serra, P.A.; L’episcopo, F.; Tirolo, C.; Caniglia, S.; Testa, N.; Gennuso, F.; Giaquinta, G.; Rocchitta, G.; Desole, M.S.; et al. Estrogen, Neuroinflammation and Neuroprotection in Parkinson’s Disease: Glia Dictates Resistance versus Vulnerability to Neurodegeneration. Neuroscience 2006, 138, 869–878. [Google Scholar] [CrossRef]
- Morissette, M.; Al Sweidi, S.; Callier, S.; Di Paolo, T. Estrogen and SERM Neuroprotection in Animal Models of Parkinson’s Disease. Mol. Cell Endocrinol. 2008, 290, 60–69. [Google Scholar] [CrossRef]
- Shulman, L.M. Is There a Connection between Estrogen and Parkinson’s Disease? Park. Relat. Disord 2002, 8, 289–295. [Google Scholar] [CrossRef]
- Baba, T.; Shimizu, T.; Suzuki, Y.; Ogawara, M.; Isono, K.; Koseki, H.; Kurosawa, H.; Shirasawa, T. Estrogen, Insulin, and Dietary Signals Cooperatively Regulate Longevity Signals to Enhance Resistance to Oxidative Stress in Mice*. J. Biol. Chem. 2005, 280, 16417–16426. [Google Scholar] [CrossRef] [Green Version]
- Popat, R.A.; Van Den Eeden, S.K.; Tanner, C.M.; McGuire, V.; Bernstein, A.L.; Bloch, D.A.; Leimpeter, A.; Nelson, L.M. Effect of Reproductive Factors and Postmenopausal Hormone Use on the Risk of Parkinson Disease. Neurology 2005, 65, 383–390. [Google Scholar] [CrossRef]
- Lee, J.; Pinares-Garcia, P.; Loke, H.; Ham, S.; Vilain, E.; Harley, V.R. Sex-Specific Neuroprotection by Inhibition of the Y-Chromosome Gene, SRY, in Experimental Parkinson’s Disease. Proc. Natl. Acad. Sci. USA 2019, 116, 16577–16582. [Google Scholar] [CrossRef] [Green Version]
- Loke, H.; Harley, V.; Lee, J. Biological Factors Underlying Sex Differences in Neurological Disorders. Int. J. Biochem. Cell Biol. 2015, 65, 139–150. [Google Scholar] [CrossRef]
- Westberg, L.; Håkansson, A.; Melke, J.; Shahabi, H.N.; Nilsson, S.; Buervenich, S.; Carmine, A.; Ahlberg, J.; Grundell, M.B.; Schulhof, B.; et al. Association between the Estrogen Receptor Beta Gene and Age of Onset of Parkinson’s Disease. Psychoneuroendocrinology 2004, 29, 993–998. [Google Scholar] [CrossRef]
- Håkansson, A.; Westberg, L.; Nilsson, S.; Buervenich, S.; Carmine, A.; Holmberg, B.; Sydow, O.; Olson, L.; Johnels, B.; Eriksson, E.; et al. Investigation of Genes Coding for Inflammatory Components in Parkinson’s Disease. Mov. Disord. 2005, 20, 569–573. [Google Scholar] [CrossRef] [PubMed]
- Maraganore, D.M.; Farrer, M.J.; McDonnell, S.K.; Elbaz, A.; Schaid, D.J.; Hardy, J.A.; Rocca, W.A. Case-Control Study of Estrogen Receptor Gene Polymorphisms in Parkinson’s Disease. Mov. Disord. 2002, 17, 509–512. [Google Scholar] [CrossRef] [PubMed]
- Alzheimer, A.; Stelzmann, R.A.; Schnitzlein, H.N.; Murtagh, F.R. An English Translation of Alzheimer’s 1907 Paper, “Uber Eine Eigenartige Erkankung Der Hirnrinde”. Clin. Anat. 1995, 8, 429–431. [Google Scholar] [CrossRef] [PubMed]
- Hardy, J.; Selkoe, D.J. The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics. Science 2002, 297, 353–356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Irwin, D.J.; Cohen, T.J.; Grossman, M.; Arnold, S.E.; Xie, S.X.; Lee, V.M.-Y.; Trojanowski, J.Q. Acetylated Tau, a Novel Pathological Signature in Alzheimer’s Disease and Other Tauopathies. Brain 2012, 135, 807–818. [Google Scholar] [CrossRef] [Green Version]
- Beam, C.R.; Kaneshiro, C.; Jang, J.Y.; Reynolds, C.A.; Pedersen, N.L.; Gatz, M. Differences Between Women and Men in Incidence Rates of Dementia and Alzheimer’s Disease. J. Alzheimers Dis. 2018, 64, 1077–1083. [Google Scholar] [CrossRef]
- Filon, J.R.; Intorcia, A.J.; Sue, L.I.; Vazquez Arreola, E.; Wilson, J.; Davis, K.J.; Sabbagh, M.N.; Belden, C.M.; Caselli, R.J.; Adler, C.H.; et al. Gender Differences in Alzheimer Disease: Brain Atrophy, Histopathology Burden, and Cognition. J. Neuropathol. Exp. Neurol. 2016, 75, 748–754. [Google Scholar] [CrossRef] [Green Version]
- Plassman, B.L.; Langa, K.M.; McCammon, R.J.; Fisher, G.G.; Potter, G.G.; Burke, J.R.; Steffens, D.C.; Foster, N.L.; Giordani, B.; Unverzagt, F.W.; et al. Incidence of Dementia and Cognitive Impairment, Not Dementia in the United States. Ann. Neurol. 2011, 70, 418–426. [Google Scholar] [CrossRef] [Green Version]
- Seshadri, S.; Wolf, P.A.; Beiser, A.; Au, R.; McNulty, K.; White, R.; D’Agostino, R.B. Lifetime Risk of Dementia and Alzheimer’s Disease. The Impact of Mortality on Risk Estimates in the Framingham Study. Neurology 1997, 49, 1498–1504. [Google Scholar] [CrossRef]
- Mielke, M.M. Sex and Gender Differences in Alzheimer’s Disease Dementia. Psychiatry Times 2018, 35, 14–17. [Google Scholar]
- Fisher, C.A.; Sewell, K.; Brown, A.; Churchyard, A. Aggression in Huntington’s Disease: A Systematic Review of Rates of Aggression and Treatment Methods. J. Huntingt. Dis. 2014, 3, 319–332. [Google Scholar] [CrossRef]
- Oveisgharan, S.; Arvanitakis, Z.; Yu, L.; Farfel, J.; Schneider, J.A.; Bennett, D.A. Sex Differences in Alzheimer’s Disease and Common Neuropathologies of Aging. Acta Neuropathol. 2018, 136, 887–900. [Google Scholar] [CrossRef]
- Buckley, R.F.; Mormino, E.C.; Rabin, J.S.; Hohman, T.J.; Landau, S.; Hanseeuw, B.J.; Jacobs, H.I.L.; Papp, K.V.; Amariglio, R.E.; Properzi, M.J.; et al. Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults. JAMA Neurol. 2019, 76, 542–551. [Google Scholar] [CrossRef] [Green Version]
- Dennison, J.L.; Ricciardi, N.R.; Lohse, I.; Volmar, C.-H.; Wahlestedt, C. Sexual Dimorphism in the 3xTg-AD Mouse Model and Its Impact on Pre-Clinical Research. J. Alzheimers Dis. 2021, 80, 41–52. [Google Scholar] [CrossRef]
- Mifflin, M.A.; Winslow, W.; Surendra, L.; Tallino, S.; Vural, A.; Velazquez, R. Sex Differences in the IntelliCage and the Morris Water Maze in the APP/PS1 Mouse Model of Amyloidosis. Neurobiol. Aging 2021, 101, 130–140. [Google Scholar] [CrossRef]
- Li, L.; Wu, X.-H.; Zhao, X.-J.; Xu, L.; Pan, C.-L.; Zhang, Z.-Y. Zerumbone Ameliorates Behavioral Impairments and Neuropathology in Transgenic APP/PS1 Mice by Suppressing MAPK Signaling. J. Neuroinflammation 2020, 17, 61. [Google Scholar] [CrossRef] [Green Version]
- Sala Frigerio, C.; Wolfs, L.; Fattorelli, N.; Thrupp, N.; Voytyuk, I.; Schmidt, I.; Mancuso, R.; Chen, W.-T.; Woodbury, M.E.; Srivastava, G.; et al. The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques. Cell Rep. 2019, 27, 1293–1306.e6. [Google Scholar] [CrossRef] [Green Version]
- Rae, E.A.; Brown, R.E. The Problem of Genotype and Sex Differences in Life Expectancy in Transgenic AD Mice. Neurosci. Biobehav. Rev. 2015, 57, 238–251. [Google Scholar] [CrossRef]
- Roy, U.; Stute, L.; Höfling, C.; Hartlage-Rübsamen, M.; Matysik, J.; Roβner, S.; Alia, A. Sex- and Age-Specific Modulation of Brain GABA Levels in a Mouse Model of Alzheimer’s Disease. Neurobiol. Aging 2018, 62, 168–179. [Google Scholar] [CrossRef]
- Kosel, F.; Pelley, J.M.S.; Franklin, T.B. Behavioural and Psychological Symptoms of Dementia in Mouse Models of Alzheimer’s Disease-Related Pathology. Neurosci. Biobehav. Rev. 2020, 112, 634–647. [Google Scholar] [CrossRef]
- Sandberg, G.; Stewart, W.; Smialek, J.; Troncoso, J.C. The Prevalence of the Neuropathological Lesions of Alzheimer’s Disease Is Independent of Race and Gender. Neurobiol. Aging 2001, 22, 169–175. [Google Scholar] [CrossRef] [PubMed]
- Corder, E.H.; Ghebremedhin, E.; Taylor, M.G.; Thal, D.R.; Ohm, T.G.; Braak, H. The Biphasic Relationship between Regional Brain Senile Plaque and Neurofibrillary Tangle Distributions: Modification by Age, Sex, and APOE Polymorphism. Ann. N. Y. Acad. Sci. 2004, 1019, 24–28. [Google Scholar] [CrossRef] [PubMed]
- Damoiseaux, J.S.; Seeley, W.W.; Zhou, J.; Shirer, W.R.; Coppola, G.; Karydas, A.; Rosen, H.J.; Miller, B.L.; Kramer, J.H.; Greicius, M.D.; et al. Gender Modulates the APOE Ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels. J. Neurosci. 2012, 32, 8254–8262. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Riedel, B.C.; Thompson, P.M.; Brinton, R.D. Age, APOE and Sex: Triad of Risk of Alzheimer’s Disease. J. Steroid. Biochem. Mol. Biol. 2016, 160, 134–147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Altmann, A.; Tian, L.; Henderson, V.W.; Greicius, M.D.; Investigators, A.D.N.I. Sex Modifies the APOE-Related Risk of Developing Alzheimer Disease. Ann. Neurol. 2014, 75, 563–573. [Google Scholar] [CrossRef] [Green Version]
- Hohman, T.J.; Dumitrescu, L.; Barnes, L.L.; Thambisetty, M.; Beecham, G.; Kunkle, B.; Gifford, K.A.; Bush, W.S.; Chibnik, L.B.; Mukherjee, S.; et al. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018, 75, 989–998. [Google Scholar] [CrossRef]
- Scheyer, O.; Rahman, A.; Hristov, H.; Berkowitz, C.; Isaacson, R.S.; Diaz Brinton, R.; Mosconi, L. Female Sex and Alzheimer’s Risk: The Menopause Connection. J. Prev. Alzheimers Dis. 2018, 5, 225–230. [Google Scholar] [CrossRef]
- Vest, R.S.; Pike, C.J. Gender, Sex Steroid Hormones, and Alzheimer’s Disease. Horm. Behav. 2013, 63, 301–307. [Google Scholar] [CrossRef] [Green Version]
- Zandi, P.P.; Carlson, M.C.; Plassman, B.L.; Welsh-Bohmer, K.A.; Mayer, L.S.; Steffens, D.C.; Breitner, J.C.S. Cache County Memory Study Investigators Hormone Replacement Therapy and Incidence of Alzheimer Disease in Older Women: The Cache County Study. JAMA 2002, 288, 2123–2129. [Google Scholar] [CrossRef] [Green Version]
- Carroll, J.C.; Rosario, E.R.; Villamagna, A.; Pike, C.J. Continuous and Cyclic Progesterone Differentially Interact with Estradiol in the Regulation of Alzheimer-Like Pathology in Female 3×Transgenic-Alzheimer’s Disease Mice. Endocrinology 2010, 151, 2713–2722. [Google Scholar] [CrossRef]
- Carroll, J.C.; Pike, C.J. Selective Estrogen Receptor Modulators Differentially Regulate Alzheimer-Like Changes in Female 3xTg-AD Mice. Endocrinology 2008, 149, 2607–2611. [Google Scholar] [CrossRef]
- Amtul, Z.; Wang, L.; Westaway, D.; Rozmahel, R.F. Neuroprotective Mechanism Conferred by 17beta-Estradiol on the Biochemical Basis of Alzheimer’s Disease. Neuroscience 2010, 169, 781–786. [Google Scholar] [CrossRef]
- Cordey, M.; Gundimeda, U.; Gopalakrishna, R.; Pike, C.J. Estrogen Activates Protein Kinase C in Neurons: Role in Neuroprotection. J. Neurochem. 2003, 84, 1340–1348. [Google Scholar] [CrossRef]
- Wang, C.; Zhang, F.; Jiang, S.; Siedlak, S.L.; Shen, L.; Perry, G.; Wang, X.; Tang, B.; Zhu, X. Estrogen Receptor-α Is Localized to Neurofibrillary Tangles in Alzheimer’s Disease. Sci. Rep. 2016, 6, 20352. [Google Scholar] [CrossRef] [Green Version]
- Tamagno, E.; Guglielmotto, M.; Monteleone, D.; Tabaton, M. Amyloid-β Production: Major Link between Oxidative Stress and BACE1. Neurotox. Res. 2012, 22, 208–219. [Google Scholar] [CrossRef]
- Alvarez-de-la-Rosa, M.; Silva, I.; Nilsen, J.; Pérez, M.M.; García-Segura, L.M.; Avila, J.; Naftolin, F. Estradiol Prevents Neural Tau Hyperphosphorylation Characteristic of Alzheimer’s Disease. Ann. N. Y. Acad. Sci. 2005, 1052, 210–224. [Google Scholar] [CrossRef]
- Xiong, J.; Kang, S.S.; Wang, Z.; Liu, X.; Kuo, T.-C.; Korkmaz, F.; Padilla, A.; Miyashita, S.; Chan, P.; Zhang, Z.; et al. FSH Blockade Improves Cognition in Mice with Alzheimer’s Disease. Nature 2022, 603, 470–476. [Google Scholar] [CrossRef]
- Asthana, S.; Baker, L.D.; Craft, S.; Stanczyk, F.Z.; Veith, R.C.; Raskind, M.A.; Plymate, S.R. High-Dose Estradiol Improves Cognition for Women with AD: Results of a Randomized Study. Neurology 2001, 57, 605–612. [Google Scholar] [CrossRef]
- Henderson, V.W.; Paganini-Hill, A.; Miller, B.L.; Elble, R.J.; Reyes, P.F.; Shoupe, D.; McCleary, C.A.; Klein, R.A.; Hake, A.M.; Farlow, M.R. Estrogen for Alzheimer’s Disease in Women: Randomized, Double-Blind, Placebo-Controlled Trial. Neurology 2000, 54, 295–301. [Google Scholar] [CrossRef]
- Wang, P.N.; Liao, S.Q.; Liu, R.S.; Liu, C.Y.; Chao, H.T.; Lu, S.R.; Yu, H.Y.; Wang, S.J.; Liu, H.C. Effects of Estrogen on Cognition, Mood, and Cerebral Blood Flow in AD: A Controlled Study. Neurology 2000, 54, 2061–2066. [Google Scholar] [CrossRef]
- Mulnard, R.A.; Cotman, C.W.; Kawas, C.; van Dyck, C.H.; Sano, M.; Doody, R.; Koss, E.; Pfeiffer, E.; Jin, S.; Gamst, A.; et al. Estrogen Replacement Therapy for Treatment of Mild to Moderate Alzheimer Disease: A Randomized Controlled Trial. Alzheimer’s Disease Cooperative Study. JAMA 2000, 283, 1007–1015. [Google Scholar] [CrossRef] [PubMed]
- Shumaker, S.A.; Legault, C.; Rapp, S.R.; Thal, L.; Wallace, R.B.; Ockene, J.K.; Hendrix, S.L.; Jones, B.N.; Assaf, A.R.; Jackson, R.D.; et al. Estrogen plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women’s Health Initiative Memory Study: A Randomized Controlled Trial. JAMA 2003, 289, 2651–2662. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rosario, E.R.; Carroll, J.C.; Oddo, S.; LaFerla, F.M.; Pike, C.J. Androgens Regulate the Development of Neuropathology in a Triple Transgenic Mouse Model of Alzheimer’s Disease. J. Neurosci. 2006, 26, 13384–13389. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rosario, E.R.; Carroll, J.C.; Pike, C.J. Evaluation of the Effects of Testosterone and Luteinizing Hormone on Regulation of β-Amyloid in Male 3xTg-AD Mice. Brain Res. 2012, 1466, 137–145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rosario, E.R.; Carroll, J.; Pike, C.J. Testosterone Regulation of Alzheimer-like Neuropathology in Male 3xTg-AD Mice Involves Both Estrogen and Androgen Pathways. Brain Res. 2010, 1359, 281–290. [Google Scholar] [CrossRef] [Green Version]
- Overk, C.R.; Lu, P.-Y.; Wang, Y.-T.; Choi, J.; Shaw, J.W.; Thatcher, G.R.; Mufson, E.J. Effects of Aromatase Inhibition versus Gonadectomy on Hippocampal Complex Amyloid Pathology in Triple Transgenic Mice. Neurobiol. Dis. 2012, 45, 479–487. [Google Scholar] [CrossRef] [Green Version]
- Köglsberger, S.; Cordero-Maldonado, M.L.; Antony, P.; Forster, J.I.; Garcia, P.; Buttini, M.; Crawford, A.; Glaab, E. Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for Tauopathies. Mol. Neurobiol. 2017, 54, 7979–7993. [Google Scholar] [CrossRef] [Green Version]
- Deming, Y.; Dumitrescu, L.; Barnes, L.L.; Thambisetty, M.; Kunkle, B.; Gifford, K.A.; Bush, W.S.; Chibnik, L.B.; Mukherjee, S.; De Jager, P.L.; et al. Sex-Specific Genetic Predictors of Alzheimer’s Disease Biomarkers. Acta Neuropathol. 2018, 136, 857–872. [Google Scholar] [CrossRef]
- Davis, E.J.; Broestl, L.; Abdulai-Saiku, S.; Worden, K.; Bonham, L.W.; Miñones-Moyano, E.; Moreno, A.J.; Wang, D.; Chang, K.; Williams, G.; et al. A Second X Chromosome Contributes to Resilience in a Mouse Model of Alzheimer’s Disease. Sci. Transl. Med. 2020, 12, eaaz5677. [Google Scholar] [CrossRef]
- Chung, J.; Das, A.; Mez, J.; Sun, X.; Chou, Y.-F.; Leung, Y.Y.; Thiagalingam, S.; Zhang, X.; Jun, G.R.; Kunkle, B.W.; et al. Genome-Wide Association and Multi-Omics Studies Identify MGMT as a Novel Risk Gene for Alzheimer Disease among Women. Alzheimers Dement. 2021, 17, e054483. [Google Scholar] [CrossRef]
- Yan, Y.; Wang, X.; Chaput, D.; Shin, M.-K.; Koh, Y.; Gan, L.; Pieper, A.A.; Woo, J.-A.A.; Kang, D.E. X-Linked Ubiquitin-Specific Peptidase 11 Increases Tauopathy Vulnerability in Women. Cell 2022, 185, 3913–3930.e19. [Google Scholar] [CrossRef]
- Jiang, Y.; Zhou, X.; Wong, H.Y.; Ouyang, L.; Ip, F.C.F.; Chau, V.M.N.; Lau, S.-F.; Wu, W.; Wong, D.Y.K.; Seo, H.; et al. An IL1RL1 Genetic Variant Lowers Soluble ST2 Levels and the Risk Effects of APOE-Ε4 in Female Patients with Alzheimer’s Disease. Nat. Aging 2022, 2, 616–634. [Google Scholar] [CrossRef]
- Frost, G.R.; Jonas, L.A.; Li, Y.-M. Friend, Foe or Both? Immune Activity in Alzheimer’s Disease. Front. Aging Neurosci. 2019, 11, 337. [Google Scholar] [CrossRef] [Green Version]
- Klein, S.L.; Flanagan, K.L. Sex Differences in Immune Responses. Nat. Rev. Immunol. 2016, 16, 626–638. [Google Scholar] [CrossRef]
- Nunomura, A.; Perry, G. RNA and Oxidative Stress in Alzheimer’s Disease: Focus on MicroRNAs. Oxidative Med. Cell. Longev. 2020, 2020, e2638130. [Google Scholar] [CrossRef]
- Selkoe, D.J.; Hardy, J. The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years. EMBO Mol. Med. 2016, 8, 595–608. [Google Scholar] [CrossRef]
- Amato, M.P.; Portaccio, E.; Goretti, B.; Zipoli, V.; Hakiki, B.; Giannini, M.; Pastò, L.; Razzolini, L. Cognitive Impairment in Early Stages of Multiple Sclerosis. Neurol. Sci. 2010, 31, S211–S214. [Google Scholar] [CrossRef]
- Mahad, D.H.; Trapp, B.D.; Lassmann, H. Pathological Mechanisms in Progressive Multiple Sclerosis. Lancet Neurol. 2015, 14, 183–193. [Google Scholar] [CrossRef]
- Reich, D.S.; Zackowski, K.M.; Gordon-Lipkin, E.M.; Smith, S.A.; Chodkowski, B.A.; Cutter, G.R.; Calabresi, P.A. Corticospinal Tract Abnormalities Are Associated with Weakness in Multiple Sclerosis. AJNR Am. J. Neuroradiol. 2008, 29, 333–339. [Google Scholar] [CrossRef] [Green Version]
- Ngo, S.T.; Steyn, F.J.; McCombe, P.A. Gender Differences in Autoimmune Disease. Front. Neuroendocrinol. 2014, 35, 347–369. [Google Scholar] [CrossRef] [Green Version]
- Spence, R.D.; Voskuhl, R.R. Neuroprotective Effects of Estrogens and Androgens in CNS Inflammation and Neurodegeneration. Front. Neuroendocr. 2012, 33, 105–115. [Google Scholar] [CrossRef] [PubMed]
- El-Etr, M.; Ghoumari, A.; Sitruk-Ware, R.; Schumacher, M. Hormonal Influences in Multiple Sclerosis: New Therapeutic Benefits for Steroids. Maturitas 2011, 68, 47–51. [Google Scholar] [CrossRef] [PubMed]
- Confavreux, C.; Vukusic, S.; Adeleine, P. Early Clinical Predictors and Progression of Irreversible Disability in Multiple Sclerosis: An Amnesic Process. Brain 2003, 126, 770–782. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Orton, S.-M.; Herrera, B.M.; Yee, I.M.; Valdar, W.; Ramagopalan, S.V.; Sadovnick, A.D.; Ebers, G.C. Canadian Collaborative Study Group Sex Ratio of Multiple Sclerosis in Canada: A Longitudinal Study. Lancet Neurol. 2006, 5, 932–936. [Google Scholar] [CrossRef] [PubMed]
- Gholipour, T.; Healy, B.; Baruch, N.F.; Weiner, H.L.; Chitnis, T. Demographic and Clinical Characteristics of Malignant Multiple Sclerosis. Neurology 2011, 76, 1996–2001. [Google Scholar] [CrossRef]
- Du Pasquier, R.A.; Pinschewer, D.D.; Merkler, D. Immunological Mechanism of Action and Clinical Profile of Disease-Modifying Treatments in Multiple Sclerosis. CNS Drugs 2014, 28, 535–558. [Google Scholar] [CrossRef]
- Dunn, S.E.; Lee, H.; Pavri, F.R.; Zhang, M.A. Sex-Based Differences in Multiple Sclerosis (Part I): Biology of Disease Incidence. In Emerging and Evolving Topics in Multiple Sclerosis Pathogenesis and Treatments; Current Topics in Behavioral Neurosciences; La Flamme, A.C., Orian, J.M., Eds.; Springer International Publishing: Cham, Switzerland, 2015; pp. 29–56. ISBN 978-3-319-25543-9. [Google Scholar]
- Gold, S.M.; Willing, A.; Leypoldt, F.; Paul, F.; Friese, M.A. Sex Differences in Autoimmune Disorders of the Central Nervous System. Semin. Immunopathol. 2019, 41, 177–188. [Google Scholar] [CrossRef]
- Voskuhl, R.R.; Patel, K.; Paul, F.; Gold, S.M.; Scheel, M.; Kuchling, J.; Cooper, G.; Asseyer, S.; Chien, C.; Brandt, A.U.; et al. Sex Differences in Brain Atrophy in Multiple Sclerosis. Biol. Sex Differ. 2020, 11, 49. [Google Scholar] [CrossRef]
- Kovats, S. Estrogen Receptors Regulate Innate Immune Cells and Signaling Pathways. Cell. Immunol. 2015, 294, 63–69. [Google Scholar] [CrossRef] [Green Version]
- Kim, R.Y.; Mangu, D.; Hoffman, A.S.; Kavosh, R.; Jung, E.; Itoh, N.; Voskuhl, R. Oestrogen Receptor β Ligand Acts on CD11c+ Cells to Mediate Protection in Experimental Autoimmune Encephalomyelitis. Brain 2018, 141, 132–147. [Google Scholar] [CrossRef] [Green Version]
- Spence, R.D.; Wisdom, A.J.; Cao, Y.; Hill, H.M.; Mongerson, C.R.L.; Stapornkul, B.; Itoh, N.; Sofroniew, M.V.; Voskuhl, R.R. Estrogen Mediates Neuroprotection and Anti-Inflammatory Effects during EAE through ERα Signaling on Astrocytes but Not through ERβ Signaling on Astrocytes or Neurons. J. Neurosci. 2013, 33, 10924–10933. [Google Scholar] [CrossRef]
- Crawford, D.K.; Mangiardi, M.; Song, B.; Patel, R.; Du, S.; Sofroniew, M.V.; Voskuhl, R.R.; Tiwari-Woodruff, S.K. Oestrogen Receptor Beta Ligand: A Novel Treatment to Enhance Endogenous Functional Remyelination. Brain 2010, 133, 2999–3016. [Google Scholar] [CrossRef]
- Khalaj, A.J.; Yoon, J.; Nakai, J.; Winchester, Z.; Moore, S.M.; Yoo, T.; Martinez-Torres, L.; Kumar, S.; Itoh, N.; Tiwari-Woodruff, S.K. Estrogen Receptor (ER) β Expression in Oligodendrocytes Is Required for Attenuation of Clinical Disease by an ERβ Ligand. Proc. Natl. Acad. Sci. USA 2013, 110, 19125–19130. [Google Scholar] [CrossRef] [Green Version]
- Moore, S.M.; Khalaj, A.J.; Kumar, S.; Winchester, Z.; Yoon, J.; Yoo, T.; Martinez-Torres, L.; Yasui, N.; Katzenellenbogen, J.A.; Tiwari-Woodruff, S.K. Multiple Functional Therapeutic Effects of the Estrogen Receptor β Agonist Indazole-Cl in a Mouse Model of Multiple Sclerosis. Proc. Natl. Acad. Sci. USA 2014, 111, 18061–18066. [Google Scholar] [CrossRef] [Green Version]
- Saijo, K.; Collier, J.G.; Li, A.C.; Katzenellenbogen, J.A.; Glass, C.K. An ADIOL-ERβ-CtBP Transrepression Pathway Negatively Regulates Microglia-Mediated Inflammation. Cell 2011, 145, 584–595. [Google Scholar] [CrossRef] [Green Version]
- Wu, W.; Tan, X.; Dai, Y.; Krishnan, V.; Warner, M.; Gustafsson, J.-Å. Targeting Estrogen Receptor β in Microglia and T Cells to Treat Experimental Autoimmune Encephalomyelitis. Proc. Natl. Acad. Sci. USA 2013, 110, 3543–3548. [Google Scholar] [CrossRef] [Green Version]
- Prossnitz, E.R.; Arterburn, J.B.; Sklar, L.A. GPR30: A G Protein-Coupled Receptor for Estrogen. Mol. Cell Endocrinol. 2007, 265–266, 138–142. [Google Scholar] [CrossRef] [Green Version]
- Giatti, S.; Rigolio, R.; Romano, S.; Mitro, N.; Viviani, B.; Cavaletti, G.; Caruso, D.; Garcia-Segura, L.M.; Melcangi, R.C. Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis. Neuroendocrinology 2015, 101, 296–308. [Google Scholar] [CrossRef]
- Hussain, R.; Ghoumari, A.M.; Bielecki, B.; Steibel, J.; Boehm, N.; Liere, P.; Macklin, W.B.; Kumar, N.; Habert, R.; Mhaouty-Kodja, S.; et al. The Neural Androgen Receptor: A Therapeutic Target for Myelin Repair in Chronic Demyelination. Brain 2013, 136, 132–146. [Google Scholar] [CrossRef]
- El-Etr, M.; Rame, M.; Boucher, C.; Ghoumari, A.M.; Kumar, N.; Liere, P.; Pianos, A.; Schumacher, M.; Sitruk-Ware, R. Progesterone and Nestorone Promote Myelin Regeneration in Chronic Demyelinating Lesions of Corpus Callosum and Cerebral Cortex. Glia 2015, 63, 104–117. [Google Scholar] [CrossRef] [Green Version]
- Garay, L.; Gonzalez Deniselle, M.C.; Sitruk-Ware, R.; Guennoun, R.; Schumacher, M.; De Nicola, A.F. Efficacy of the Selective Progesterone Receptor Agonist Nestorone for Chronic Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2014, 276, 89–97. [Google Scholar] [CrossRef] [PubMed]
- Massa, M.G.; David, C.; Jörg, S.; Berg, J.; Gisevius, B.; Hirschberg, S.; Linker, R.A.; Gold, R.; Haghikia, A. Testosterone Differentially Affects T Cells and Neurons in Murine and Human Models of Neuroinflammation and Neurodegeneration. Am. J. Pathol. 2017, 187, 1613–1622. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bove, R.; Chitnis, T. The Role of Gender and Sex Hormones in Determining the Onset and Outcome of Multiple Sclerosis. Mult. Scler. 2014, 20, 520–526. [Google Scholar] [CrossRef] [PubMed]
- Org, E.; Mehrabian, M.; Parks, B.W.; Shipkova, P.; Liu, X.; Drake, T.A.; Lusis, A.J. Sex Differences and Hormonal Effects on Gut Microbiota Composition in Mice. Gut Microbes 2016, 7, 313–322. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Markle, J.G.; Fish, E.N. SeXX Matters in Immunity. Trends Immunol. 2014, 35, 97–104. [Google Scholar] [CrossRef]
- Hooten, K.G.; Beers, D.R.; Zhao, W.; Appel, S.H. Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis. Neurotherapeutics 2015, 12, 364–375. [Google Scholar] [CrossRef] [Green Version]
- Rowland, L.P.; Shneider, N.A. Amyotrophic Lateral Sclerosis. N. Engl. J. Med. 2001, 344, 1688–1700. [Google Scholar] [CrossRef]
- Bilsland, L.G.; Sahai, E.; Kelly, G.; Golding, M.; Greensmith, L.; Schiavo, G. Deficits in Axonal Transport Precede ALS Symptoms in Vivo. Proc. Natl. Acad. Sci. USA 2010, 107, 20523–20528. [Google Scholar] [CrossRef] [Green Version]
- Brites, D.; Vaz, A.R. Microglia Centered Pathogenesis in ALS: Insights in Cell Interconnectivity. Front. Cell Neurosci. 2014, 8, 117. [Google Scholar] [CrossRef] [Green Version]
- Turner, B.J.; Cheah, I.K.; Macfarlane, K.J.; Lopes, E.C.; Petratos, S.; Langford, S.J.; Cheema, S.S. Antisense Peptide Nucleic Acid-Mediated Knockdown of the P75 Neurotrophin Receptor Delays Motor Neuron Disease in Mutant SOD1 Transgenic Mice. J. Neurochem. 2003, 87, 752–763. [Google Scholar] [CrossRef]
- McCombe, P.A.; Henderson, R.D. Effects of Gender in Amyotrophic Lateral Sclerosis. Gend. Med. 2010, 7, 557–570. [Google Scholar] [CrossRef]
- Talbott, E.O.; Malek, A.M.; Lacomis, D. The Epidemiology of Amyotrophic Lateral Sclerosis. Handb. Clin. Neurol. 2016, 138, 225–238. [Google Scholar] [CrossRef]
- Couratier, P.; Corcia, P.; Lautrette, G.; Nicol, M.; Preux, P.-M.; Marin, B. Epidemiology of Amyotrophic Lateral Sclerosis: A Review of Literature. Rev. Neurol. 2016, 172, 37–45. [Google Scholar] [CrossRef]
- Zarei, S.; Carr, K.; Reiley, L.; Diaz, K.; Guerra, O.; Altamirano, P.F.; Pagani, W.; Lodin, D.; Orozco, G.; Chinea, A. A Comprehensive Review of Amyotrophic Lateral Sclerosis. Surg. Neurol. Int. 2015, 6, 171. [Google Scholar] [CrossRef] [Green Version]
- Snow, R.J.; Turnbull, J.; da Silva, S.; Jiang, F.; Tarnopolsky, M.A. Creatine Supplementation and Riluzole Treatment Provide Similar Beneficial Effects in Copper, Zinc Superoxide Dismutase (G93A) Transgenic Mice. Neuroscience 2003, 119, 661–667. [Google Scholar] [CrossRef]
- Hayworth, C.R.; Gonzalez-Lima, F. Pre-Symptomatic Detection of Chronic Motor Deficits and Genotype Prediction in Congenic B6.SOD1(G93A) ALS Mouse Model. Neuroscience 2009, 164, 975–985. [Google Scholar] [CrossRef] [Green Version]
- Manjaly, Z.R.; Scott, K.M.; Abhinav, K.; Wijesekera, L.; Ganesalingam, J.; Goldstein, L.H.; Janssen, A.; Dougherty, A.; Willey, E.; Stanton, B.R.; et al. The Sex Ratio in Amyotrophic Lateral Sclerosis: A Population Based Study. Amyotroph. Lateral Scler. 2010, 11, 439–442. [Google Scholar] [CrossRef]
- de Jong, S.; Huisman, M.; Sutedja, N.; van der Kooi, A.; de Visser, M.; Schelhaas, J.; van der Schouw, Y.; Veldink, J.; van den Berg, L. Endogenous Female Reproductive Hormones and the Risk of Amyotrophic Lateral Sclerosis. J. Neurol. 2013, 260, 507–512. [Google Scholar] [CrossRef]
- Choi, C.-I.; Lee, Y.-D.; Gwag, B.J.; Cho, S.I.; Kim, S.-S.; Suh-Kim, H. Effects of Estrogen on Lifespan and Motor Functions in Female HSOD1 G93A Transgenic Mice. J. Neurol. Sci. 2008, 268, 40–47. [Google Scholar] [CrossRef]
- Groeneveld, G.J.; Van Muiswinkel, F.L.; Sturkenboom, J.M.; Wokke, J.H.J.; Bär, P.R.; Van den Berg, L.H. Ovariectomy and 17beta-Estradiol Modulate Disease Progression of a Mouse Model of ALS. Brain Res. 2004, 1021, 128–131. [Google Scholar] [CrossRef]
- Yan, L.; Liu, Y.; Sun, C.; Zheng, Q.; Hao, P.; Zhai, J.; Liu, Y. Effects of Ovariectomy in an HSOD1-G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis (ALS). Med. Sci. Monit. 2018, 24, 678–686. [Google Scholar] [CrossRef] [PubMed]
- Popat, R.A.; Van Den Eeden, S.K.; Tanner, C.M.; Bernstein, A.L.; Bloch, D.A.; Leimpeter, A.; McGuire, V.; Nelson, L.M. Effect of Reproductive Factors and Postmenopausal Hormone Use on the Risk of Amyotrophic Lateral Sclerosis. Neuroepidemiology 2006, 27, 117–121. [Google Scholar] [CrossRef] [PubMed]
- Rooney, J.; Fogh, I.; Westeneng, H.-J.; Vajda, A.; McLaughlin, R.; Heverin, M.; Jones, A.; van Eijk, R.; Calvo, A.; Mazzini, L.; et al. C9orf72 Expansion Differentially Affects Males with Spinal Onset Amyotrophic Lateral Sclerosis. J. Neurol. Neurosurg. Psychiatry 2017, 88, 281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pape, J.A.; Grose, J.H. The Effects of Diet and Sex in Amyotrophic Lateral Sclerosis. Rev. Neurol. 2020, 176, 301–315. [Google Scholar] [CrossRef] [PubMed]
- van den Berg, L.H.; Sorenson, E.; Gronseth, G.; Macklin, E.A.; Andrews, J.; Baloh, R.H.; Benatar, M.; Berry, J.D.; Chio, A.; Corcia, P.; et al. Revised Airlie House Consensus Guidelines for Design and Implementation of ALS Clinical Trials. Neurology 2019, 92, e1610–e1623. [Google Scholar] [CrossRef] [Green Version]
- Murdock, B.J.; Goutman, S.A.; Boss, J.; Kim, S.; Feldman, E.L. Amyotrophic Lateral Sclerosis Survival Associates with Neutrophils in a Sex-Specific Manner. Neurol. Neuroimmunol. Neuroinflamm. 2021, 8, e953. [Google Scholar] [CrossRef]
- Lopez-Lee, C.; Kodama, L.; Gan, L. Sex Differences in Neurodegeneration: The Role of the Immune System in Humans. Biol. Psychiatry 2022, 91, 72–80. [Google Scholar] [CrossRef]
- Santiago, J.A.; Quinn, J.P.; Potashkin, J.A. Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients. Int. J. Mol. Sci. 2021, 22, 7150. [Google Scholar] [CrossRef]
- Pegoraro, V.; Merico, A.; Angelini, C. Micro-RNAs in ALS Muscle: Differences in Gender, Age at Onset and Disease Duration. J. Neurol. Sci. 2017, 380, 58–63. [Google Scholar] [CrossRef] [Green Version]
- Williams, A.H.; Valdez, G.; Moresi, V.; Qi, X.; McAnally, J.; Elliott, J.L.; Bassel-Duby, R.; Sanes, J.R.; Olson, E.N. MicroRNA-206 Delays ALS Progression and Promotes Regeneration of Neuromuscular Synapses in Mice. Science 2009, 326, 1549–1554. [Google Scholar] [CrossRef] [Green Version]
- Wang, X.H. MicroRNA in Myogenesis and Muscle Atrophy. Curr. Opin. Clin. Nutr. Metab. Care 2013, 16, 258–266. [Google Scholar] [CrossRef]
- Ma, G.; Wang, Y.; Li, Y.; Cui, L.; Zhao, Y.; Zhao, B.; Li, K. MiR-206, a Key Modulator of Skeletal Muscle Development and Disease. Int. J. Biol. Sci. 2015, 11, 345–352. [Google Scholar] [CrossRef]
- Bates, G.P.; Dorsey, R.; Gusella, J.F.; Hayden, M.R.; Kay, C.; Leavitt, B.R.; Nance, M.; Ross, C.A.; Scahill, R.I.; Wetzel, R.; et al. Huntington Disease. Nat. Rev. Dis. Prim. 2015, 1, 15005. [Google Scholar] [CrossRef]
- Walker, F.O. Huntington’s Disease. Lancet 2007, 369, 218–228. [Google Scholar] [CrossRef]
- Kehoe, P.; Krawczak, M.; Harper, P.S.; Owen, M.J.; Jones, A.L. Age of Onset in Huntington Disease: Sex Specific Influence of Apolipoprotein E Genotype and Normal CAG Repeat Length. J. Med. Genet. 1999, 36, 108–111. [Google Scholar]
- Meoni, S.; Macerollo, A.; Moro, E. Sex Differences in Movement Disorders. Nat. Rev. Neurol. 2020, 16, 84–96. [Google Scholar] [CrossRef]
- Weydt, P.; Soyal, S.M.; Landwehrmeyer, G.B.; Patsch, W. For the European Huntington Disease Network a Single Nucleotide Polymorphism in the Coding Region of PGC-1α Is a Male-Specific Modifier of Huntington Disease Age-at-Onset in a Large European Cohort. BMC Neurol. 2014, 14, 1. [Google Scholar] [CrossRef] [Green Version]
- Zielonka, D.; Ren, M.; De Michele, G.; Roos, R.A.C.; Squitieri, F.; Bentivoglio, A.R.; Marcinkowski, J.T.; Landwehrmeyer, G.B. The Contribution of Gender Differences in Motor, Behavioral and Cognitive Features to Functional Capacity, Independence and Quality of Life in Patients with Huntington’s Disease. Park. Relat. Disord. 2018, 49, 42–47. [Google Scholar] [CrossRef]
- Pringsheim, T.; Wiltshire, K.; Day, L.; Dykeman, J.; Steeves, T.; Jette, N. The Incidence and Prevalence of Huntington’s Disease: A Systematic Review and Meta-Analysis. Mov. Disord. 2012, 27, 1083–1091. [Google Scholar] [CrossRef]
- Dorner, J.L.; Miller, B.R.; Barton, S.J.; Brock, T.J.; Rebec, G.V. Sex Differences in Behavior and Striatal Ascorbate Release in the 140 CAG Knock-in Mouse Model of Huntington’s Disease. Behav. Brain Res. 2007, 178, 90–97. [Google Scholar] [CrossRef] [Green Version]
- Bode, F.J.; Stephan, M.; Suhling, H.; Pabst, R.; Straub, R.H.; Raber, K.A.; Bonin, M.; Nguyen, H.P.; Riess, O.; Bauer, A.; et al. Sex Differences in a Transgenic Rat Model of Huntington’s Disease: Decreased 17beta-Estradiol Levels Correlate with Reduced Numbers of DARPP32+ Neurons in Males. Hum. Mol. Genet. 2008, 17, 2595–2609. [Google Scholar] [CrossRef] [PubMed]
- Connor, B.; Sun, Y.; von Hieber, D.; Tang, S.K.; Jones, K.S.; Maucksch, C. AAV1/2-Mediated BDNF Gene Therapy in a Transgenic Rat Model of Huntington’s Disease. Gene 2016, 23, 283–295. [Google Scholar] [CrossRef] [PubMed]
- Padovan-Neto, F.E.; Jurkowski, L.; Murray, C.; Stutzmann, G.E.; Kwan, M.; Ghavami, A.; Beaumont, V.; Park, L.C.; West, A.R. Age- and Sex-Related Changes in Cortical and Striatal Nitric Oxide Synthase in the Q175 Mouse Model of Huntington’s Disease. Nitric Oxide 2019, 83, 40–50. [Google Scholar] [CrossRef] [PubMed]
- Bruzelius, E.; Scarpa, J.; Zhao, Y.; Basu, S.; Faghmous, J.H.; Baum, A. Huntington’s Disease in the United States: Variation by Demographic and Socioeconomic Factors. Mov. Disord. 2019, 34, 858–865. [Google Scholar] [CrossRef] [PubMed]
- Zielonka, D.; Marinus, J.; Roos, R.A.C.; De Michele, G.; Di Donato, S.; Putter, H.; Marcinkowski, J.; Squitieri, F.; Bentivoglio, A.R.; Landwehrmeyer, G.B. The Influence of Gender on Phenotype and Disease Progression in Patients with Huntington’s Disease. Park. Relat. Disord. 2013, 19, 192–197. [Google Scholar] [CrossRef]
- Marder, K.; Zhao, H.; Myers, R.H.; Cudkowicz, M.; Kayson, E.; Kieburtz, K.; Orme, C.; Paulsen, J.; Penney, J.B.; Siemers, E.; et al. Rate of Functional Decline in Huntington’s Disease. Huntington Study Group. Neurology 2000, 54, 452–458. [Google Scholar] [CrossRef]
- Duff, K.; Paulsen, J.S.; Beglinger, L.J.; Langbehn, D.R.; Stout, J.C. Predict-HD Investigators of the Huntington Study Group Psychiatric Symptoms in Huntington’s Disease before Diagnosis: The Predict-HD Study. Biol. Psychiatry 2007, 62, 1341–1346. [Google Scholar] [CrossRef]
- Kirkwood, S.C.; Su, J.L.; Conneally, P.; Foroud, T. Progression of Symptoms in the Early and Middle Stages of Huntington Disease. Arch. Neurol. 2001, 58, 273–278. [Google Scholar] [CrossRef] [Green Version]
- Hentosh, S.; Zhu, L.; Patino, J.; Furr, J.W.; Rocha, N.P.; Furr Stimming, E. Sex Differences in Huntington’s Disease: Evaluating the Enroll-HD Database. Mov. Disord. Clin. Pr. 2021, 8, 420–426. [Google Scholar] [CrossRef]
- Epping, E.A.; Mills, J.A.; Beglinger, L.J.; Fiedorowicz, J.G.; Craufurd, D.; Smith, M.M.; Groves, M.; Bijanki, K.R.; Downing, N.; Williams, J.K.; et al. Characterization of Depression in Prodromal Huntington Disease in the Neurobiological Predictors of HD (PREDICT-HD) Study. J. Psychiatr. Res. 2013, 47, 1423–1431. [Google Scholar] [CrossRef] [Green Version]
- van Duijn, E.; Craufurd, D.; Hubers, A.A.M.; Giltay, E.J.; Bonelli, R.; Rickards, H.; Anderson, K.E.; van Walsem, M.R.; van der Mast, R.C.; Orth, M.; et al. Neuropsychiatric Symptoms in a European Huntington’s Disease Cohort (REGISTRY). J. Neurol. Neurosurg. Psychiatry 2014, 85, 1411–1418. [Google Scholar] [CrossRef] [Green Version]
- Dale, M.; Maltby, J.; Shimozaki, S.; Cramp, R.; Rickards, H. REGISTRY Investigators of the European Huntington’s Disease Network Disease Stage, but Not Sex, Predicts Depression and Psychological Distress in Huntington’s Disease: A European Population Study. J. Psychosom. Res. 2016, 80, 17–22. [Google Scholar] [CrossRef]
- van der Hoek, T.C.; Bus, B.A.A.; Matui, P.; van der Marck, M.A.; Esselink, R.A.; Tendolkar, I. Prevalence of Depression in Parkinson’s Disease: Effects of Disease Stage, Motor Subtype and Gender. J. Neurol. Sci. 2011, 310, 220–224. [Google Scholar] [CrossRef]
- Beal, C.C.; Stuifbergen, A.K.; Brown, A. Depression in Multiple Sclerosis: A Longitudinal Analysis. Arch. Psychiatr. Nurs. 2007, 21, 181–191. [Google Scholar] [CrossRef] [Green Version]
- Pang, T.Y.C.; Du, X.; Zajac, M.S.; Howard, M.L.; Hannan, A.J. Altered Serotonin Receptor Expression Is Associated with Depression-Related Behavior in the R6/1 Transgenic Mouse Model of Huntington’s Disease. Hum. Mol. Genet. 2009, 18, 753–766. [Google Scholar] [CrossRef] [Green Version]
- Renoir, T.; Zajac, M.S.; Du, X.; Pang, T.Y.; Leang, L.; Chevarin, C.; Lanfumey, L.; Hannan, A.J. Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington’s Disease and Depression. PLoS ONE 2011, 6, e22133. [Google Scholar] [CrossRef]
- Du, X.; Leang, L.; Mustafa, T.; Renoir, T.; Pang, T.Y.; Hannan, A.J. Environmental Enrichment Rescues Female-Specific Hyperactivity of the Hypothalamic-Pituitary-Adrenal Axis in a Model of Huntington’s Disease. Transl. Psychiatry 2012, 2, e133. [Google Scholar] [CrossRef] [Green Version]
- Hannan, A.J.; Ransome, M.I. Deficits in Spermatogenesis but Not Neurogenesis Are Alleviated by Chronic Testosterone Therapy in R6/1 Huntington’s Disease Mice. J. Neuroendocrinol. 2012, 24, 341–356. [Google Scholar] [CrossRef]
- Markianos, M.; Panas, M.; Kalfakis, N.; Vassilopoulos, D. Plasma Testosterone in Male Patients with Huntington’s Disease: Relations to Severity of Illness and Dementia. Ann. Neurol. 2005, 57, 520–525. [Google Scholar] [CrossRef]
- Markianos, M.; Panas, M.; Kalfakis, N.; Vassilopoulos, D. Plasma Testosterone, Dehydroepiandrosterone Sulfate, and Cortisol in Female Patients with Huntington’s Disease. Neuro. Endocrinol. Lett. 2007, 28, 199–203. [Google Scholar]
- Zarrouf, F.A.; Artz, S.; Griffith, J.; Sirbu, C.; Kommor, M. Testosterone and Depression: Systematic Review and Meta-Analysis. J. Psychiatr. Pract. 2009, 15, 289–305. [Google Scholar] [CrossRef] [PubMed]
- Baksu, B.; Baksu, A.; Göker, N.; Citak, S. Do Different Delivery Systems of Hormone Therapy Have Different Effects on Psychological Symptoms in Surgically Menopausal Women? A Randomized Controlled Trial. Maturitas 2009, 62, 140–145. [Google Scholar] [CrossRef]
- Studd, J.; Panay, N. Are Oestrogens Useful for the Treatment of Depression in Women? Best Pract. Res. Clin. Obstet. Gynaecol. 2009, 23, 63–71. [Google Scholar] [CrossRef] [PubMed]
- Warlow, C.; Sudlow, C.; Dennis, M.; Wardlaw, J.; Sandercock, P. Stroke. Lancet 2003, 362, 1211–1224. [Google Scholar] [CrossRef] [PubMed]
- Golomb, M.R.; Fullerton, H.J.; Nowak-Gottl, U.; Deveber, G. International Pediatric Stroke Study Group Male Predominance in Childhood Ischemic Stroke: Findings from the International Pediatric Stroke Study. Stroke 2009, 40, 52–57. [Google Scholar] [CrossRef] [Green Version]
- Alkayed, N.J.; Harukuni, I.; Kimes, A.S.; London, E.D.; Traystman, R.J.; Hurn, P.D. Gender-Linked Brain Injury in Experimental Stroke. Stroke 1998, 29, 159–165; discussion 166. [Google Scholar] [CrossRef] [Green Version]
- Liu, F.; McCullough, L.D. Interactions between Age, Sex, and Hormones in Experimental Ischemic Stroke. Neurochem. Int. 2012, 61, 1255–1265. [Google Scholar] [CrossRef] [Green Version]
- Murphy, S.J.; McCullough, L.D.; Smith, J.M. Stroke in the Female: Role of Biological Sex and Estrogen. ILAR J. 2004, 45, 147–159. [Google Scholar] [CrossRef]
- Spychala, M.S.; Honarpisheh, P.; McCullough, L.D. Sex Differences in Neuroinflammation and Neuroprotection in Ischemic Stroke. J. Neurosci. Res. 2017, 95, 462–471. [Google Scholar] [CrossRef] [Green Version]
- Ostadal, B.; Ostadal, P. Sex-Based Differences in Cardiac Ischaemic Injury and Protection: Therapeutic Implications. Br. J. Pharmacol. 2014, 171, 541–554. [Google Scholar] [CrossRef] [Green Version]
- Cordeau, P.; Lalancette-Hébert, M.; Weng, Y.C.; Kriz, J. Estrogen Receptors Alpha Mediates Postischemic Inflammation in Chronically Estrogen-Deprived Mice. Neurobiol. Aging 2016, 40, 50–60. [Google Scholar] [CrossRef]
- Chauhan, A.; Moser, H.; McCullough, L.D. Sex Differences in Ischaemic Stroke: Potential Cellular Mechanisms. Clin. Sci. 2017, 131, 533–552. [Google Scholar] [CrossRef]
- McCullough, L.D.; Hurn, P.D. Estrogen and Ischemic Neuroprotection: An Integrated View. Trends Endocrinol. Metab. 2003, 14, 228–235. [Google Scholar] [CrossRef]
- Shichita, T.; Ito, M.; Yoshimura, A. Post-Ischemic Inflammation Regulates Neural Damage and Protection. Front. Cell Neurosci. 2014, 8, 319. [Google Scholar] [CrossRef]
- Iadecola, C.; Anrather, J. The Immunology of Stroke: From Mechanisms to Translation. Nat. Med. 2011, 17, 796–808. [Google Scholar] [CrossRef]
- Kerr, N.; Dietrich, D.W.; Bramlett, H.M.; Raval, A.P. Sexually Dimorphic Microglia and Ischemic Stroke. CNS Neurosci. 2019, 25, 1308–1317. [Google Scholar] [CrossRef]
- Villa, R.F.; Ferrari, F.; Moretti, A. Post-Stroke Depression: Mechanisms and Pharmacological Treatment. Pharmacol. Ther. 2018, 184, 131–144. [Google Scholar] [CrossRef]
- Lenz, K.M.; Nelson, L.H. Microglia and Beyond: Innate Immune Cells as Regulators of Brain Development and Behavioral Function. Front. Immunol. 2018, 9, 698. [Google Scholar] [CrossRef] [Green Version]
- Lenz, K.M.; McCarthy, M.M. A Starring Role for Microglia in Brain Sex Differences. Neuroscientist 2015, 21, 306–321. [Google Scholar] [CrossRef] [Green Version]
- Colton, C.A. Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain. J. Neuroimmune Pharm. 2009, 4, 399–418. [Google Scholar] [CrossRef] [Green Version]
- Correale, J. The Role of Microglial Activation in Disease Progression. Mult. Scler. 2014, 20, 1288–1295. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Colonna, M.; Butovsky, O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu. Rev. Immunol. 2017, 35, 441–468. [Google Scholar] [CrossRef] [PubMed]
- Song, G.J.; Suk, K. Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases. Front. Aging Neurosci. 2017, 9, 139. [Google Scholar] [CrossRef] [PubMed]
- Guo, S.; Wang, H.; Yin, Y. Microglia Polarization from M1 to M2 in Neurodegenerative Diseases. Front. Aging Neurosci. 2022, 14, 815347. [Google Scholar] [CrossRef] [PubMed]
- Guruswamy, R.; ElAli, A. Complex Roles of Microglial Cells in Ischemic Stroke Pathobiology: New Insights and Future Directions. Int. J. Mol. Sci. 2017, 18, 496. [Google Scholar] [CrossRef] [Green Version]
- Xiong, X.; Xu, L.; Wei, L.; White, R.E.; Ouyang, Y.-B.; Giffard, R.G. IL-4 Is Required for Sex Differences in Vulnerability to Focal Ischemia in Mice. Stroke 2015, 46, 2271–2276. [Google Scholar] [CrossRef] [Green Version]
- Fels, J.A.; Manfredi, G. Sex Differences in Ischemia/Reperfusion Injury: The Role of Mitochondrial Permeability Transition. Neurochem. Res. 2019, 44, 2336–2345. [Google Scholar] [CrossRef]
- Demarest, T.G.; Schuh, R.A.; Waddell, J.; McKenna, M.C.; Fiskum, G. Sex-Dependent Mitochondrial Respiratory Impairment and Oxidative Stress in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy. J. Neurochem. 2016, 137, 714–729. [Google Scholar] [CrossRef] [Green Version]
- Manwani, B.; Bentivegna, K.; Benashski, S.E.; Venna, V.R.; Xu, Y.; Arnold, A.P.; McCullough, L.D. Sex Differences in Ischemic Stroke Sensitivity Are Influenced by Gonadal Hormones, Not by Sex Chromosome Complement. J. Cereb. Blood Flow Metab. 2015, 35, 221–229. [Google Scholar] [CrossRef] [Green Version]
- McCullough, L.D.; Mirza, M.A.; Xu, Y.; Bentivegna, K.; Steffens, E.B.; Ritzel, R.; Liu, F. Stroke Sensitivity in the Aged: Sex Chromosome Complement vs. Gonadal Hormones. Aging 2016, 8, 1432–1441. [Google Scholar] [CrossRef] [Green Version]
- Paneni, F.; Diaz, C.C.; Libby, P.; Lüscher, T.F.; Camici, G.G. The Aging Cardiovascular System. J. Am. Coll. Cardiol. 2017, 69, 1952–1967. [Google Scholar] [CrossRef]
- Camici, P.G.; d’Amati, G.; Rimoldi, O. Coronary Microvascular Dysfunction: Mechanisms and Functional Assessment. Nat. Rev. Cardiol. 2015, 12, 48–62. [Google Scholar] [CrossRef]
- Selvamani, A.; Williams, M.H.; Miranda, R.C.; Sohrabji, F. Circulating MiRNA Profiles Provide a Biomarker for Severity of Stroke Outcomes Associated with Age and Sex in a Rat Model. Clin. Sci. 2014, 127, 77–89. [Google Scholar] [CrossRef]
- Kaidonis, G.; Rao, A.N.; Ouyang, Y.-B.; Stary, C.M. Elucidating Sex Differences in Response to Cerebral Ischemia: Immunoregulatory Mechanisms and the Role of MicroRNAs. Prog. Neurobiol. 2019, 176, 73–85. [Google Scholar] [CrossRef]
- Ma, C.; Yin, L. Neuroprotective Effect of Angiotensin II Type 2 Receptor during Cerebral Ischemia/Reperfusion. Neural Regen. Res. 2016, 11, 1102–1107. [Google Scholar] [CrossRef]
- Bushnell, C.D.; Chaturvedi, S.; Gage, K.R.; Herson, P.S.; Hurn, P.D.; Jiménez, M.C.; Kittner, S.J.; Madsen, T.E.; McCullough, L.D.; McDermott, M.; et al. Sex Differences in Stroke: Challenges and Opportunities. J. Cereb. Blood Flow Metab. 2018, 38, 2179–2191. [Google Scholar] [CrossRef]
- Netto, C.A.; Sanches, E.; Odorcyk, F.K.; Duran-Carabali, L.E.; Weis, S.N. Sex-Dependent Consequences of Neonatal Brain Hypoxia-Ischemia in the Rat. J. Neurosci. Res. 2017, 95, 409–421. [Google Scholar] [CrossRef] [Green Version]
- Nijboer, C.H.A.; Kavelaars, A.; van Bel, F.; Heijnen, C.J.; Groenendaal, F. Gender-Dependent Pathways of Hypoxia-Ischemia-Induced Cell Death and Neuroprotection in the Immature P3 Rat. Dev. Neurosci. 2007, 29, 385–392. [Google Scholar] [CrossRef]
- Renolleau, S.; Fau, S.; Charriaut-Marlangue, C. Gender-Related Differences in Apoptotic Pathways after Neonatal Cerebral Ischemia. Neuroscientist 2008, 14, 46–52. [Google Scholar] [CrossRef]
- Zhu, T.; Yao, Q.; Wang, W.; Yao, H.; Chao, J. INOS Induces Vascular Endothelial Cell Migration and Apoptosis Via Autophagy in Ischemia/Reperfusion Injury. CPB 2016, 38, 1575–1588. [Google Scholar] [CrossRef]
- Li, J.; McCullough, L.D. Sex Differences in Minocycline-Induced Neuroprotection after Experimental Stroke. J. Cereb. Blood Flow Metab. 2009, 29, 670–674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, R.; Yang, S.-H. Window of Opportunity: Estrogen as a Treatment for Ischemic Stroke. Brain Res. 2013, 1514, 83–90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liao, S.-L.; Chen, W.-Y.; Chen, C.-J. Estrogen Attenuates Tumor Necrosis Factor-α Expression to Provide Ischemic Neuroprotection in Female Rats. Neurosci. Lett. 2002, 330, 159–162. [Google Scholar] [CrossRef]
- Li, J.; Siegel, M.; Yuan, M.; Zeng, Z.; Finnucan, L.; Persky, R.; Hurn, P.D.; McCullough, L.D. Estrogen Enhances Neurogenesis and Behavioral Recovery after Stroke. J. Cereb. Blood Flow Metab. 2011, 31, 413–425. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chiappetta, O.; Gliozzi, M.; Siviglia, E.; Amantea, D.; Morrone, L.A.; Berliocchi, L.; Bagetta, G.; Corasaniti, M.T. Evidence to Implicate Early Modulation of Interleukin-1β Expression in the Neuroprotection Afforded by 17β-Estradiol in Male Rats Undergone Transient Middle Cerebral Artery Occlusion. In International Review of Neurobiology; Neuroinflammation in Neuronal Death and Repair; Academic Press: Cambridge, MA, USA, 2007; Volume 82, pp. 357–372. [Google Scholar]
- Rahimian, R.; Cordeau, P.; Kriz, J. Brain Response to Injuries: When Microglia Go Sexist. Neuroscience 2019, 405, 14–23. [Google Scholar] [CrossRef]
- Suzuki, S.; Gerhold, L.M.; Böttner, M.; Rau, S.W.; Dela Cruz, C.; Yang, E.; Zhu, H.; Yu, J.; Cashion, A.B.; Kindy, M.S.; et al. Estradiol Enhances Neurogenesis Following Ischemic Stroke through Estrogen Receptors α and β. J. Comp. Neurol. 2007, 500, 1064–1075. [Google Scholar] [CrossRef]
- Cheng, J.; Hu, W.; Toung, T.J.; Zhang, Z.; Parker, S.M.; Roselli, C.E.; Hurn, P.D. Age-Dependent Effects of Testosterone in Experimental Stroke. J. Cereb. Blood Flow Metab. 2009, 29, 486–494. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Zalewska, T.; Pawelec, P.; Ziabska, K.; Ziemka-Nalecz, M. Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia. Biomolecules 2023, 13, 26. https://doi.org/10.3390/biom13010026
Zalewska T, Pawelec P, Ziabska K, Ziemka-Nalecz M. Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia. Biomolecules. 2023; 13(1):26. https://doi.org/10.3390/biom13010026
Chicago/Turabian StyleZalewska, Teresa, Paulina Pawelec, Karolina Ziabska, and Malgorzata Ziemka-Nalecz. 2023. "Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia" Biomolecules 13, no. 1: 26. https://doi.org/10.3390/biom13010026
APA StyleZalewska, T., Pawelec, P., Ziabska, K., & Ziemka-Nalecz, M. (2023). Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia. Biomolecules, 13(1), 26. https://doi.org/10.3390/biom13010026