阿尔茨海默病病理发生中的性别差异
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摘要
阿尔茨海默病(Alzheimer's disease,AD)是一种神经退行性疾病,严重威胁着人类健康.流行病学研究表明,性别与AD发病风险密切相关,女性AD发病率显著高于同龄男性.了解AD病理发生中的性别差异,对于揭示AD发生的规律与特点具有重要的意义.本文就AD病理发生中的性别差异及社会学、生物学等相关原因进行了分析,并论述了针对性别差异的药物防治AD的研究进展,以期为基于性别差异的AD防治提供新思路.
Alzheimer's disease(AD) is a neurodegenerative disease, which is a serious threat to human health.Epidemiological studies show that the females are related to the higher risk of AD incidence. Therefore, it is of great significance to explore the regularity and characteristics of AD in view of gender difference in AD pathogenesis. This article summarizes the sex difference in the pathogenesis of AD and the related factors involved in sex-dependent AD incidence, and discusses the progress of the research on the prevention and treatment of AD based on the gender difference, hopefully providing new approach for AD therapy.
Alzheimer's disease(AD) is a neurodegenerative disease, which is a serious threat to human health.Epidemiological studies show that the females are related to the higher risk of AD incidence. Therefore, it is of great significance to explore the regularity and characteristics of AD in view of gender difference in AD pathogenesis. This article summarizes the sex difference in the pathogenesis of AD and the related factors involved in sex-dependent AD incidence, and discusses the progress of the research on the prevention and treatment of AD based on the gender difference, hopefully providing new approach for AD therapy.
引文
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[3]Han X,Aenlle K K,Bean LA,et al.Role of estrogen receptorαandβin preserving hippocampal function during aging.Journal of Neuroscience,2013,33(6):2671-2683
[4]Lv W,Du N,Liu Y,et al.Low Testosterone level and risk of Alzheimer's disease in the elderly men:a systematic review and meta-analysis.Molecular Neurobiology,2016,53(4):2679-2684
[5]Nead K T,Gaskin G,Chester C,et al.Androgen deprivation therapy and future Alzheimer's disease risk.Journal of Clinical Oncology,2016,34(6):566-571
[6]Yun J,Yeo I J,Hwang C J,et al.Estrogen deficiency exacerbates Aβ-induced memory impairment through enhancement of neuroinflammation,amylodogenesis and NF-κB activation in ovariectomized mice.Brain,Behavior,and Immunity,2018,73:282-293
[7]刘健康,彭韵桦,龙建纲.脑内线粒体雌激素受体β在女性阿尔茨海默病发生过程中的作用.生物化学与生物物理进展,2012,39(8):785-790Liu J K,Peng Y H,Long J G.Prog Biochem Biophys,2012,39(8):785-790
[8]Hou C,Peng Y,Qin C,et al.Hydrogen-rich water improves cognitive impairment gender-dependently in APP/PS1 mice without affecting Aβclearance.Free Radical Research,2018,52(11-12):1311-1322
[9]Peng Y,Hou C,Yang Z,et al.Hydroxytyrosol mildly improve cognitive function independent of APP processing in APP/PS1mice.Molecular Nutrition&Food Research,2016,60(11):2331-2342
[10]Jia J,Wang F,Wei C,et al.The prevalence of dementia in urban and rural areas of China.Alzheimers&Dementia,2014,10(1):1-9
[11]Li J Q,Tan L,Wang H F,et al.Risk factors for predicting progression from mild cognitive impairment to Alzheimer's disease:a systematic review and meta-analysis of cohort studies.Journal of Neurology Neurosurgery&Psychiatry,2016,87(5):476-484
[12]Nomaguchi K M,Bianchi S M.Exercise time:gender differences in the effects of marriage,parenthood,and employment.Journal of Marriage&Family,2004,66(2):413-430
[13]Hogervorst E,Clifford A,Stock J,et al.Exercise to prevent cognitive decline and Alzheimer's disease:for whom,when,what,and(most importantly)how much?.Journal of Alzheimer's Disease&Parkinsonism,2013,02(3):1-8
[14]Middleton L E,Barnes D E,Lui LY,et al.Physical activity over the life course and its association with cognitive performance and impairment in old age.Journal of the American Geriatrics Society,2010,58(7):1322-1326
[15]邓莉,王今朝,杨莉等.胆碱转运体与阿尔茨海默病.生物化学与生物物理进展,2014,41(12):1207-1213Deng L,Wang J Z,Yang L,et al.Prog Biochem Biophys,2014,41(12):1207-1213
[16]Moreno-Gonzalez I,Estrada L D,Sanchez-Mejias E,et al.Smoking exacerbates amyloid pathology in a mouse model of Alzheimer's disease.Nature Communications,2013,4(1):1-8
[17]Sotiropoulos I,Silva J,Kimura T,et al.Female hippocampus vulnerability to environmental stress,a precipitating factor in Tau aggregation pathology.Journal of Alzheimers Disease,2015,43(3):763-774
[18]Organization W H.Global Health Observatory(GHO)Data.2016[2018-09-11].https://www.who.int/
[19]Association A S.2013 Alzheimer's disease facts and figures.Alzheimers&Dementia,2013,9(2):208-245
[20]Nettiksimmons J,Tranah G,Evans D S,et al.Gene-based aggregate SNP associations between candidate AD genes and cognitive decline.AGE,2016,38(2):41
[21]Schellenberg G D,Montine T J.The genetics and neuropathology of Alzheimer's disease.Acta Neuropathologica,2012,124(3):305-323
[22]Wang C,Najm R,Xu Q,et al.Gain of toxic apolipoprotein E4effects in human iPSC-derived neurons is ameliorated by a smallmolecule structure corrector.Nature Medicine,2018,24(5):647-657
[23]Damoiseaux J S,Seeley W W,Zhou J,et al.Gender modulates the APOE4 effect in healthy older adults:convergent evidence from functional brain connectivity and spinal fluid tau levels.Journal of Neuroscience,2012,32(24):8254-8262
[24]Riley K P,Snowdon D A,Markesbery W R.Alzheimer's neurofibrillary pathology and the spectrum of cognitive function:findings from the Nun Study.Annals of Neurology,2010,51(5):567-577
[25]Giedd J N,Raznahan A,Mills K L,et al.Review:magnetic resonance imaging of male/female differences in human adolescent brain anatomy.Biology of Sex Differences,2012,3(1):19
[26]Skup M,Zhu H,Wang Y,et al.Sex differences in grey matter atrophy patterns among AD and aMCI patients:results from ADNI.Neuroimage,2011,56(3):890-906
[27]Ritchie S J,Cox S R,Shen X,et al.Sex differences in the adult human brain:evidence from 5216 UK biobank participants.Cerebral Cortex,2018,28(8):2959-2975
[28]Hsieh T C,Lin W Y,Ding H J,et al.Sex-and age-related differences in brain FDG metabolism of healthy adults:an SPManalysis.Journal of Neuroimaging,2012,22(1):21-27
[29]Perneczky R,Diehl-Schmid J,F?rstl H,et al.Male gender is associated with greater cerebral hypometabolism in frontotemporal dementia:evidence for sex-related cognitive reserve.International Journal of Geriatric Psychiatry,2010,22(11):1135-1140
[30]Lentini E,Kasahara M,Arver S,et al.Sex differences in the human brain and the impact of sex chromosomes and sex hormones.Cerebral Cortex,2013,23(10):2322-2336
[31]Brinton R D.Estrogen-induced plasticity from cells to circuits:predictions for cognitive function.Trends in Pharmacological Sciences,2009,30(4):212-222
[32]Aenlle K K,Kumar A,Cui L,et al.Estrogen effects on cognition and hippocampal transcription in middle-aged mice.Neurobiology ofAging,2009,30(6):932-945
[33]Yue X,Lu M,Lancaster T,et al.Brain estrogen deficiency accelerates A plaque formation in an Alzheimer's disease animal model.Proc NatAcad Sci USA,2006,102(52):19198-19203
[34]Simpkins J W,Yi K D,Yang S H,et al.Mitochondrial mechanisms of estrogen neuroprotection.BBA-General Subjects,2010,1800(10):1113-1120
[35]Zhao L,Brinton R D.Estrogen receptor alpha and beta differentially regulate intracellular Ca(2+)dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons.Brain Research,2007,1172(5):48-59
[36]George S,Petit G H,Gouras G K,et al.Nonsteroidal selective androgen receptor modulators and selective estrogen receptorβagonists moderate cognitive deficits and amyloid-βlevels in a mouse model of Alzheimer's disease.Acs Chemical Neuroscience,2011,4(12):1537-1548
[37]Wilkins H M,Mahnken J D,Welch P,et al.A mitochondrial biomarker-based study of S-equol in Alzheimer's diseasesubjects:results of a single-arm,pilot trial.Journal of Alzheimers Disease Jad,2017,59(1):291-300
[38]Tang Y.Early inflammation-associated factors blunt sterol regulatory element-binding proteins-1-mediated lipogenesis in high-fat diet-fed APP SWE/PSEN1dE9 mouse model of Alzheimer's disease.Journal of Neurochemistry,2016,136(4):791-803
[39]Shi L,Zhao D,Hou C,et al.Early interleukin-6 enhances hepatic ketogenesis in APPSWE/PSEN1dE9 mice via 3-hydroxy-3-methylglutary-CoA synthase 2 signaling activation by p38/nuclear factorκB p65.Neurobiology ofAging,2017,56(1):115-126
[40]Pines,A.Alzheimer's disease,menopause and the impact of the estrogenic environment.Climacteric,2016,19(5):430-432
[41]Imtiaz B,Tuppurainen M,Rikkonen T,et al.Postmenopausal hormone therapy and Alzheimer disease:a prospective cohort study.Alzheimers&Dementia the Journal of the Alzheimers Association,2015,11(7):1062-1068
[42]Feldman HA,Longcope C,Derby CA,et al.Age trends in the level of serum testosterone and other hormones in middle-aged men:longitudinal results from the Massachusetts male aging study.JClin Endocrinol Metab,2015,87(2):589-598
[43]Song L,Li X,Bai X X,et al.Calycosin improves cognitive function in a transgenic mouse model of Alzheimer's disease by activating the protein kinase C pathway.Neural Regeneration Research,2017,12(11):1870-1876
[44]Tschiffely A E,Schuh R A,Prokai-Tatrai K,et al.An exploratory investigation of brain-selective estrogen treatment in males using a mouse model of Alzheimer's disease.Hormones and Behavior,2018,98(1):16-21
[45]Hou M,Fu Y J,Liu C,et al.Effects of extractionfrom raspberry on hippocampus proteomics of mice suffered from ovariectomizedinduced AD.China Journal of Chinese Materia Medica,2016,41(15):2895-2900
[46]Diaz A,Trevi?o S,Vázquez-Roque R,et al.The aminoestrogen prolame increases recognition memory and hippocampal neuronal spine density in aged mice.Synapse,2017,10(71):1-8
[47]Jiménez-Rubio G,Herrera-Pérez J J,Hernández-Hernández O T,et al.Relationship between androgen deficiency and memory impairment in aging and Alzheimer's disease.Actas Esp Psiquiatr,2017,45(5):227-247
[48]Vaizura M N,Imanirwana S,Chin K Y.A Review on the Effects of testosterone supplementation in hypogonadal men with cognitive impairment.Current Drug Targets,2017,19(8):898-906
[49]Yao P L,Zhuo S,Mei H,et al.Androgen alleviates neurotoxicity ofβ-amyloid peptide(Aβ)by promoting microglial clearance of Aβand inhibiting microglial inflammatory response to Aβ.Cns Neuroscience&Therapeutics,2017,23(11):855-865
[50]Lee J H,Byun M S,Yi D,et al.Sex-specific association of sex hormones and gonadotropins,with brain amyloid and hippocampal neurodegeneration.Neurobiology of Aging,2017,58(1):34-40
[51]Soultanov V,Fedotova J,Nikitina T,et al.Antidepressant-Like Effect of Ropren?inβ-amyloid-(25-35)rat model of Alzheimer's disease with altered levels of androgens.Molecular Neurobiology,2017,54(4):2611-2621
[52]李宏军;周宝林;白丽莉,等.老年男性痴呆病人雄激素补充治疗初探.中华男科学杂志,2003(03):193-196Li H J,Zhou B L,Bai L L,et al.National Journal of Andrology,2003,9(3):193-196
[53]Cho J H,Jung J Y,Lee B J,et al.Epimedii herba:a promising herbal medicine for neuroplasticity.Phytotherapy Research,2017,31(6):838-848
[54]李林,张兰.中药治疗阿尔茨海默病的作用特点.生物化学与生物物理进展,2012,39(8):816-828Li L,Zhang L.Prog Biochem Biophys,2012,39(8):816-828
[2]Erol R,Brooker D,Peel E.Women and Dementia:A Global Research Review.2015[2018-09-11].https://www.alz.co.uk/
[3]Han X,Aenlle K K,Bean LA,et al.Role of estrogen receptorαandβin preserving hippocampal function during aging.Journal of Neuroscience,2013,33(6):2671-2683
[4]Lv W,Du N,Liu Y,et al.Low Testosterone level and risk of Alzheimer's disease in the elderly men:a systematic review and meta-analysis.Molecular Neurobiology,2016,53(4):2679-2684
[5]Nead K T,Gaskin G,Chester C,et al.Androgen deprivation therapy and future Alzheimer's disease risk.Journal of Clinical Oncology,2016,34(6):566-571
[6]Yun J,Yeo I J,Hwang C J,et al.Estrogen deficiency exacerbates Aβ-induced memory impairment through enhancement of neuroinflammation,amylodogenesis and NF-κB activation in ovariectomized mice.Brain,Behavior,and Immunity,2018,73:282-293
[7]刘健康,彭韵桦,龙建纲.脑内线粒体雌激素受体β在女性阿尔茨海默病发生过程中的作用.生物化学与生物物理进展,2012,39(8):785-790Liu J K,Peng Y H,Long J G.Prog Biochem Biophys,2012,39(8):785-790
[8]Hou C,Peng Y,Qin C,et al.Hydrogen-rich water improves cognitive impairment gender-dependently in APP/PS1 mice without affecting Aβclearance.Free Radical Research,2018,52(11-12):1311-1322
[9]Peng Y,Hou C,Yang Z,et al.Hydroxytyrosol mildly improve cognitive function independent of APP processing in APP/PS1mice.Molecular Nutrition&Food Research,2016,60(11):2331-2342
[10]Jia J,Wang F,Wei C,et al.The prevalence of dementia in urban and rural areas of China.Alzheimers&Dementia,2014,10(1):1-9
[11]Li J Q,Tan L,Wang H F,et al.Risk factors for predicting progression from mild cognitive impairment to Alzheimer's disease:a systematic review and meta-analysis of cohort studies.Journal of Neurology Neurosurgery&Psychiatry,2016,87(5):476-484
[12]Nomaguchi K M,Bianchi S M.Exercise time:gender differences in the effects of marriage,parenthood,and employment.Journal of Marriage&Family,2004,66(2):413-430
[13]Hogervorst E,Clifford A,Stock J,et al.Exercise to prevent cognitive decline and Alzheimer's disease:for whom,when,what,and(most importantly)how much?.Journal of Alzheimer's Disease&Parkinsonism,2013,02(3):1-8
[14]Middleton L E,Barnes D E,Lui LY,et al.Physical activity over the life course and its association with cognitive performance and impairment in old age.Journal of the American Geriatrics Society,2010,58(7):1322-1326
[15]邓莉,王今朝,杨莉等.胆碱转运体与阿尔茨海默病.生物化学与生物物理进展,2014,41(12):1207-1213Deng L,Wang J Z,Yang L,et al.Prog Biochem Biophys,2014,41(12):1207-1213
[16]Moreno-Gonzalez I,Estrada L D,Sanchez-Mejias E,et al.Smoking exacerbates amyloid pathology in a mouse model of Alzheimer's disease.Nature Communications,2013,4(1):1-8
[17]Sotiropoulos I,Silva J,Kimura T,et al.Female hippocampus vulnerability to environmental stress,a precipitating factor in Tau aggregation pathology.Journal of Alzheimers Disease,2015,43(3):763-774
[18]Organization W H.Global Health Observatory(GHO)Data.2016[2018-09-11].https://www.who.int/
[19]Association A S.2013 Alzheimer's disease facts and figures.Alzheimers&Dementia,2013,9(2):208-245
[20]Nettiksimmons J,Tranah G,Evans D S,et al.Gene-based aggregate SNP associations between candidate AD genes and cognitive decline.AGE,2016,38(2):41
[21]Schellenberg G D,Montine T J.The genetics and neuropathology of Alzheimer's disease.Acta Neuropathologica,2012,124(3):305-323
[22]Wang C,Najm R,Xu Q,et al.Gain of toxic apolipoprotein E4effects in human iPSC-derived neurons is ameliorated by a smallmolecule structure corrector.Nature Medicine,2018,24(5):647-657
[23]Damoiseaux J S,Seeley W W,Zhou J,et al.Gender modulates the APOE4 effect in healthy older adults:convergent evidence from functional brain connectivity and spinal fluid tau levels.Journal of Neuroscience,2012,32(24):8254-8262
[24]Riley K P,Snowdon D A,Markesbery W R.Alzheimer's neurofibrillary pathology and the spectrum of cognitive function:findings from the Nun Study.Annals of Neurology,2010,51(5):567-577
[25]Giedd J N,Raznahan A,Mills K L,et al.Review:magnetic resonance imaging of male/female differences in human adolescent brain anatomy.Biology of Sex Differences,2012,3(1):19
[26]Skup M,Zhu H,Wang Y,et al.Sex differences in grey matter atrophy patterns among AD and aMCI patients:results from ADNI.Neuroimage,2011,56(3):890-906
[27]Ritchie S J,Cox S R,Shen X,et al.Sex differences in the adult human brain:evidence from 5216 UK biobank participants.Cerebral Cortex,2018,28(8):2959-2975
[28]Hsieh T C,Lin W Y,Ding H J,et al.Sex-and age-related differences in brain FDG metabolism of healthy adults:an SPManalysis.Journal of Neuroimaging,2012,22(1):21-27
[29]Perneczky R,Diehl-Schmid J,F?rstl H,et al.Male gender is associated with greater cerebral hypometabolism in frontotemporal dementia:evidence for sex-related cognitive reserve.International Journal of Geriatric Psychiatry,2010,22(11):1135-1140
[30]Lentini E,Kasahara M,Arver S,et al.Sex differences in the human brain and the impact of sex chromosomes and sex hormones.Cerebral Cortex,2013,23(10):2322-2336
[31]Brinton R D.Estrogen-induced plasticity from cells to circuits:predictions for cognitive function.Trends in Pharmacological Sciences,2009,30(4):212-222
[32]Aenlle K K,Kumar A,Cui L,et al.Estrogen effects on cognition and hippocampal transcription in middle-aged mice.Neurobiology ofAging,2009,30(6):932-945
[33]Yue X,Lu M,Lancaster T,et al.Brain estrogen deficiency accelerates A plaque formation in an Alzheimer's disease animal model.Proc NatAcad Sci USA,2006,102(52):19198-19203
[34]Simpkins J W,Yi K D,Yang S H,et al.Mitochondrial mechanisms of estrogen neuroprotection.BBA-General Subjects,2010,1800(10):1113-1120
[35]Zhao L,Brinton R D.Estrogen receptor alpha and beta differentially regulate intracellular Ca(2+)dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons.Brain Research,2007,1172(5):48-59
[36]George S,Petit G H,Gouras G K,et al.Nonsteroidal selective androgen receptor modulators and selective estrogen receptorβagonists moderate cognitive deficits and amyloid-βlevels in a mouse model of Alzheimer's disease.Acs Chemical Neuroscience,2011,4(12):1537-1548
[37]Wilkins H M,Mahnken J D,Welch P,et al.A mitochondrial biomarker-based study of S-equol in Alzheimer's diseasesubjects:results of a single-arm,pilot trial.Journal of Alzheimers Disease Jad,2017,59(1):291-300
[38]Tang Y.Early inflammation-associated factors blunt sterol regulatory element-binding proteins-1-mediated lipogenesis in high-fat diet-fed APP SWE/PSEN1dE9 mouse model of Alzheimer's disease.Journal of Neurochemistry,2016,136(4):791-803
[39]Shi L,Zhao D,Hou C,et al.Early interleukin-6 enhances hepatic ketogenesis in APPSWE/PSEN1dE9 mice via 3-hydroxy-3-methylglutary-CoA synthase 2 signaling activation by p38/nuclear factorκB p65.Neurobiology ofAging,2017,56(1):115-126
[40]Pines,A.Alzheimer's disease,menopause and the impact of the estrogenic environment.Climacteric,2016,19(5):430-432
[41]Imtiaz B,Tuppurainen M,Rikkonen T,et al.Postmenopausal hormone therapy and Alzheimer disease:a prospective cohort study.Alzheimers&Dementia the Journal of the Alzheimers Association,2015,11(7):1062-1068
[42]Feldman HA,Longcope C,Derby CA,et al.Age trends in the level of serum testosterone and other hormones in middle-aged men:longitudinal results from the Massachusetts male aging study.JClin Endocrinol Metab,2015,87(2):589-598
[43]Song L,Li X,Bai X X,et al.Calycosin improves cognitive function in a transgenic mouse model of Alzheimer's disease by activating the protein kinase C pathway.Neural Regeneration Research,2017,12(11):1870-1876
[44]Tschiffely A E,Schuh R A,Prokai-Tatrai K,et al.An exploratory investigation of brain-selective estrogen treatment in males using a mouse model of Alzheimer's disease.Hormones and Behavior,2018,98(1):16-21
[45]Hou M,Fu Y J,Liu C,et al.Effects of extractionfrom raspberry on hippocampus proteomics of mice suffered from ovariectomizedinduced AD.China Journal of Chinese Materia Medica,2016,41(15):2895-2900
[46]Diaz A,Trevi?o S,Vázquez-Roque R,et al.The aminoestrogen prolame increases recognition memory and hippocampal neuronal spine density in aged mice.Synapse,2017,10(71):1-8
[47]Jiménez-Rubio G,Herrera-Pérez J J,Hernández-Hernández O T,et al.Relationship between androgen deficiency and memory impairment in aging and Alzheimer's disease.Actas Esp Psiquiatr,2017,45(5):227-247
[48]Vaizura M N,Imanirwana S,Chin K Y.A Review on the Effects of testosterone supplementation in hypogonadal men with cognitive impairment.Current Drug Targets,2017,19(8):898-906
[49]Yao P L,Zhuo S,Mei H,et al.Androgen alleviates neurotoxicity ofβ-amyloid peptide(Aβ)by promoting microglial clearance of Aβand inhibiting microglial inflammatory response to Aβ.Cns Neuroscience&Therapeutics,2017,23(11):855-865
[50]Lee J H,Byun M S,Yi D,et al.Sex-specific association of sex hormones and gonadotropins,with brain amyloid and hippocampal neurodegeneration.Neurobiology of Aging,2017,58(1):34-40
[51]Soultanov V,Fedotova J,Nikitina T,et al.Antidepressant-Like Effect of Ropren?inβ-amyloid-(25-35)rat model of Alzheimer's disease with altered levels of androgens.Molecular Neurobiology,2017,54(4):2611-2621
[52]李宏军;周宝林;白丽莉,等.老年男性痴呆病人雄激素补充治疗初探.中华男科学杂志,2003(03):193-196Li H J,Zhou B L,Bai L L,et al.National Journal of Andrology,2003,9(3):193-196
[53]Cho J H,Jung J Y,Lee B J,et al.Epimedii herba:a promising herbal medicine for neuroplasticity.Phytotherapy Research,2017,31(6):838-848
[54]李林,张兰.中药治疗阿尔茨海默病的作用特点.生物化学与生物物理进展,2012,39(8):816-828Li L,Zhang L.Prog Biochem Biophys,2012,39(8):816-828
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