阿尔兹海默症靶向治疗方案的研究进展
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摘要
阿尔茨海默病(Alzheimer disease, AD)是一种发病机制尚未完全阐明的慢性神经退行性疾病,其最主要的病理特点是细胞内的神经元纤维缠结(neurofibrillary tangles, NFTs),以及细胞外部β淀粉样蛋白(amyloidβ-peptide,Aβ)沉积所形成的老年斑。AD患者临床表现有记忆力逐渐下降和日常行为能力的逐渐丧失,之后进展为长期记忆缺陷。AD的长期性对患者、患者的家庭甚至整个社会都造成了巨大的感情和财政负担。而其可能的致病因素也众说纷纭,但是已经明确发现的致病因素有Aβ蛋白沉积、炎症反应、线粒体功能障碍、氧化应激损伤、Tau蛋白异常的磷酸化等等。从AD发病机制出发,以相应的病理因素为靶点,开发出具有新的药理活性的药物正在被人们广泛关注。本文主要讨论了近些年来一些治疗AD的研究进展,旨在为药物研发提供新的策略和方向。
Alzheimer's disease(AD) is a chronic neurodegenerative disease which pathogenesis has not been fully elucidated.Its main pathological features are intracellular formation of neurofibrillary tangles(NFTs) and senile plaques formed by deposition of external amyloid β-peptide(Aβ).The clinical manifestations of AD patients have a gradual decline in memory and a gradual loss of daily behavioral ability,eventually progressing to long-term memory deficits.The long-term nature of AD has caused enormous emotional and financial burdens on patients,families of patients,and even society as a whole.The possible pathogenic factors are also widely discussed,but the pathogenic factors that have been clearly identified are Aβ protein deposition,inflammatory response,mitochondrial dysfunction,oxidative stress damage,and abnormal phosphorylation of Tau protein.Starting from the pathogenesis of AD,with the corresponding pathological factors as the target,the development of drugs with new pharmacological activities is underway.This article mainly discusses some research progress in the treatment of AD in recent years,aiming to provide new strategies and directions for future drug development.
Alzheimer's disease(AD) is a chronic neurodegenerative disease which pathogenesis has not been fully elucidated.Its main pathological features are intracellular formation of neurofibrillary tangles(NFTs) and senile plaques formed by deposition of external amyloid β-peptide(Aβ).The clinical manifestations of AD patients have a gradual decline in memory and a gradual loss of daily behavioral ability,eventually progressing to long-term memory deficits.The long-term nature of AD has caused enormous emotional and financial burdens on patients,families of patients,and even society as a whole.The possible pathogenic factors are also widely discussed,but the pathogenic factors that have been clearly identified are Aβ protein deposition,inflammatory response,mitochondrial dysfunction,oxidative stress damage,and abnormal phosphorylation of Tau protein.Starting from the pathogenesis of AD,with the corresponding pathological factors as the target,the development of drugs with new pharmacological activities is underway.This article mainly discusses some research progress in the treatment of AD in recent years,aiming to provide new strategies and directions for future drug development.
引文
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[8]Yan R,Vassar R.Targeting theβsecretase BACE1 for Alzheimer's disease therapy[J].The Lancet Neurology,2014,13(3):319-329.
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[12]Piton M,Hirtz C,Desmetz C,et al.Alzheimer's Disease:Advances in Drug Development[J].Journal of Alzheimer's Disease,2018,(Preprint):1-11.
[13]Nalivaeva N N,Beckett C,Belyaev N D,et al.Are amyloid degrading enzymes viable therapeutic targets in Alzheimer's disease?[J].Journal of neurochemistry,2012,120(s1):167-185.
[14]Saito T,Iwata N,Tsubuki S,et al.Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation[J].Nature medicine,2005,11(4):434-439.
[15]Deane R,Sagare A,Zlokovic B.The role of the cell surface LRPand soluble LRP in blood-brain barrier Aβclearance in Alzheimer's disease[J].Current pharmaceutical design,2008,14(16):1601-1605.
[16]Deane R J.Is RAGE still a therapeutic target for Alzheimer's disease?[J].Future medicinal chemistry,2012,4(7):915-925.
[17]Xu X-Y,Deng C-Q,Wang J,et al.Plasma levels of soluble receptor for advanced glycation end products in Alzheimer's disease[J].International Journal of Neuroscience,2017,127(5):454-458.
[18]Aisen P S,Gauthier S,Ferris S H,et al.Tramiprosate in mild-tomoderateAlzheimer'sdisease-arandomized,double-blind,placebocontrolled,multi-centre study(the Alphase Study)[J].Archives of medical science:AMS,2011,7(1):102.
[19]Gupta-Bansal R,Frederickson R C,Brunden K R.Proteoglycan-mediated Inhibition of AβProteolysis A Potential Cause Ause of Senile Plaque Accumulation[J].Journal of Biological Chemistry,1995,270(31):18666-18671.
[20]Hey J A,Jeremy Y Y,Versavel M,et al.Clinical pharmacokinetics and safety of ALZ-801,a novel prodrug of tramiprosate in development for the treatment of Alzheimer's Disease[J].Clinical pharmacokinetics,2018,57(3):315-333.
[21]Kocis P,Tolar M,Yu J,et al.Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer's disease:integrating molecular analytical methods,pharmacokinetic and clinical data[J].CNS drugs,2017,31(6):495-509.
[22]Dasilva K A,Brown M E,Cousins J E,et al.scyllo-inositol(EL-ND005)ameliorates amyloid pathology in an aggressive mouse model ofAlzheimer's disease[J].Alzheimer's&Dementia:The Journal of the Alzheimer's Association,2009,5(4):425.
[23]Chauhan V,Ji L,Chauhan A.Anti-amyloidogenic,anti-oxidant and anti-apoptotic role of gelsolin in Alzheimer's disease[J].Biogerontology,2008,9(6):381-389.
[24]Luc Buée,Thierry Bussière,Valérie Buée-Scherrer,et al.Buée L,Bussière T,Buée-Scherrer V,Delacourte A,Hof PR.Tau protein isoforms,phosphorylation and role in neurodegenerative disorders[J].Brain Research Reviews,2000,33(1):95-130.
[25]West S,Bhugra P.Emerging drug targets for Aβand tau in Alzheimer's disease:a systematic review[J].British journal of clinical pharmacology,2015,80(2):221-234.
[26]Garcia M L,Cleveland D W.Going new places using an old MAP:tau,microtubules and human neurodegenerative disease[J].Current opinion in cell biology,2001,13(1):41-48.
[27]Katja Hochgr fe,Sydow A,Matenia D,et al.Preventive methylene blue treatment preserves cognition in mice expressing fulllength pro-aggregant human Tau[J].Acta neuropathologica communications,2015,3(1):25.
[28]Ponce-Lopez T,Hong E,Abascal-D AZ M,et al.Role of GSK3βand PP2A on regulation of Tau phosphorylation in hippocampusandmemoryimpairmentinICV-STZanimalmodelofAlzheimer's disease[J].Advances in Alzheimer's Disease,2017,6(1):13.
[29]Engel T,Paloma Go i-Oliver,JoséJ.Lucas,et al.Chronic lithium administration to FTDP 17 tau and GSK 3βoverexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation,but pre formed neurofibrillary tangles do not revert[J]Journal of neurochemistry,2006,99(6):1445-1455.
[30]Shemesh E,Rudich A,Harman-Boehm I,et al.Effect of intranasal insulin on cognitive function:a systematic review[J].The Journal of Clinical Endocrinology&Metabolism,2012,97(2):366-376.
[31]Anand R,Gill K D,Mahdi A A.Therapeutics of Alzheimer's disease:Past,present and future[J].Neuropharmacology,2014,76(PA):27-50.
[32]Gourmaud S,Paquet C,Dumurgier J,et al.Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology:links to cognitive decline[J].Journal of psychiatry&neuroscience:JPN,2015,40(3):151.
[33]Zhou Q,Wang M,Du Y,et al.Inhibition of c Jun N terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice[J].Annals of neurology,2015,77(4):637-654.
[34]Corcoran N M,Martin D,Hutter-Paier B,et al.Sodium selenate specifically activates PP2A phosphatase,dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model[J].Journal of Clinical Neuroscience,2010,17(8):1025-1033.
[35]Dickey C A,Kamal A,Lundgren K,et al.The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins[J].The Journal of clinical investigation2007,117(3):648-658.
[36]Ma Q-L,Zuo X,Yang F,et al.Curcumin suppresses soluble tau dimers and corrects molecular chaperone,synaptic,and behavioral deficits in aged human tau transgenic mice[J].Journal of Biological Chemistry,2013,288(6):4056-4065.
[37]Serafini M M,Catanzaro M,Rosini M,et al.Curcumin in Alzheimer's disease:Can we think to new strategies and perspectives for this molecule?[J].Pharmacological research,2017,124:146-155.
[38]Zhang B,Maiti A,Shively S,et al.Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model[J].Proceedingsüa n~of the National Academy of Sciences of the United States of America,2005,102(1):227-231.
[39]Monacelli F,Cea M,Borghi R,et al.Do cancer drugs counteract neurodegeneration?Repurposing for alzheimer's disease[J].Journal of Alzheimer's Disease,2017,55(4):1295-1306.
[40]Brunden K R,Zhang B,Carroll J,et al.Epothilone D improves microtubule density,axonal integrity,and cognition in a transgenic mouse model of tauopathy[J].Journal of Neuroscience,2010,30(41):13861-13866.
[41]Matsuoka Y,Jouroukhin Y,Gray A J,et al.A neuronal microtubule-interacting agent,NAPVSIPQ,reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer's disease[J].Journal of Pharmacology and Experimental Therapeutics,2008,325(1):146-153.
[42]Moreira P,Cardoso S,Santos M,et al.The key role of mitochondria in Alzheimer's disease[J].Journal of Alzheimer's Disease,2006,9(2):101-110.
[43]Moreira P I,Santos M S,Oliveira C R.Alzheimer's disease:a lesson from mitochondrial dysfunction[J].Antioxidants&redox signaling,2007,9(10):1621-1630.
[44]Cottrell D,Borthwick G,Johnson M,et al.The role of cytochrome c oxidase deficient hippocampal neurones in Alzheimer's disease[J].Neuropathology and applied neurobiology,2002,28(5):390-396.
[45]Lee J,Boo J H,Ryu H.The failure of mitochondria leads to neurodegeneration:Do mitochondria need a jump start?[J].Advanced drug delivery reviews,2009,61(14):1316-1323.
[46]Tauskela J S.MitoQ-a mitochondria-targeted antioxidant[J].IDrugs:the investigational drugs journal,2007,10(6):399-412.
[47]Smith R A,Adlam V J,Blaikie F H,et al.Mitochondria targeted antioxidants in the treatment of disease[J].Annals of the New York Academy of Sciences,2008,1147(1):105-111.
[48]Manczak M,Mao P,Calkins M J,et al.Mitochondria-targeted antioxidants protect against amyloid-βtoxicity in Alzheimer's disease neurons[J].Journal of Alzheimer's Disease,2010,20(s2):S609-S631.
[49]Ba I T V,Ruitenberg A,Hofman A,et al.Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease[J].New England Journal of Medicine,2001,345(21):1515-1521.
[50]Deardorff W J,Grossberg G T.Targeting neuroinflammation in Alzheimer's disease:evidence for NSAIDs and novel therapeutics[J].Expert review of neurotherapeutics,2017,17(1):17-32.
[51]Weggen S,Eriksen J L,Das P,et al.A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity[J].Nature,2001,414(6860):212.
[2]Haass C,Steiner H.Alzheimer diseaseγ-secretase:a complex story of GxGD-type presenilin proteases[J].Trends in cell biology,2002,12(12):556-562.
[3]Holmes C,Boche D,Wilkinson D,et al.Long-term effects of Aβ42 immunisation in Alzheimer's disease:follow-up of a randomised,placebo-controlled phase I trial[J].The Lancet,2008,372(9634):216-223.
[4]Ghosh A K,Bilcer G,Harword C,et al.Structure-based design:potent inhibitors of human brain memapsin 2(β-secretase)[J].Journal of medicinal chemistry,2001,44(18):2865-2868.
[5]Chiang K,Koo E H.Emerging therapeutics for Alzheimer's disease[J]Annual Review of Pharmacology&Toxicology,2014,54(1):381.
[6]Ghosh A K,Brindisi M,Tang J.Developing beta-secretase inhibitors for treatment of Alzheimer's disease[J].J Neurochem,2012120(Suppl 1):71-83.
[7]May P C,Willis B A,Lowe S L,et al.The potent BACE1 inhibitor LY2886721 elicits robust central Aβpharmacodynamic responses in mice,dogs,and humans[J].Journal of Neuroscience,2015,35(3):1199-1210.
[8]Yan R,Vassar R.Targeting theβsecretase BACE1 for Alzheimer's disease therapy[J].The Lancet Neurology,2014,13(3):319-329.
[9]P Imbimbo B,AM Giardina G.γ-secretase inhibitors and modulators for the treatment of Alzheimer's disease:disappointments and hopes[J].Current topics in medicinal chemistry,2011,11(12):1555-1570.
[10]Kumar A,Singh A,Ekavali.A review on Alzheimer's disease pathophysiology and its management:an update[J].Pharmacological reports:PR,2015,67(2):195-203.
[11]Martone R L,Zhou H,Atchison K,et al.Begacestat(GSI-953):a novel,selective thiophene sulfonamide inhibitor of amyloid precursor proteinγ-secretase for the treatment of Alzheimer's disease[J].Journal of Pharmacology and Experimental Therapeutics,2009,331(2):598-608.
[12]Piton M,Hirtz C,Desmetz C,et al.Alzheimer's Disease:Advances in Drug Development[J].Journal of Alzheimer's Disease,2018,(Preprint):1-11.
[13]Nalivaeva N N,Beckett C,Belyaev N D,et al.Are amyloid degrading enzymes viable therapeutic targets in Alzheimer's disease?[J].Journal of neurochemistry,2012,120(s1):167-185.
[14]Saito T,Iwata N,Tsubuki S,et al.Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation[J].Nature medicine,2005,11(4):434-439.
[15]Deane R,Sagare A,Zlokovic B.The role of the cell surface LRPand soluble LRP in blood-brain barrier Aβclearance in Alzheimer's disease[J].Current pharmaceutical design,2008,14(16):1601-1605.
[16]Deane R J.Is RAGE still a therapeutic target for Alzheimer's disease?[J].Future medicinal chemistry,2012,4(7):915-925.
[17]Xu X-Y,Deng C-Q,Wang J,et al.Plasma levels of soluble receptor for advanced glycation end products in Alzheimer's disease[J].International Journal of Neuroscience,2017,127(5):454-458.
[18]Aisen P S,Gauthier S,Ferris S H,et al.Tramiprosate in mild-tomoderateAlzheimer'sdisease-arandomized,double-blind,placebocontrolled,multi-centre study(the Alphase Study)[J].Archives of medical science:AMS,2011,7(1):102.
[19]Gupta-Bansal R,Frederickson R C,Brunden K R.Proteoglycan-mediated Inhibition of AβProteolysis A Potential Cause Ause of Senile Plaque Accumulation[J].Journal of Biological Chemistry,1995,270(31):18666-18671.
[20]Hey J A,Jeremy Y Y,Versavel M,et al.Clinical pharmacokinetics and safety of ALZ-801,a novel prodrug of tramiprosate in development for the treatment of Alzheimer's Disease[J].Clinical pharmacokinetics,2018,57(3):315-333.
[21]Kocis P,Tolar M,Yu J,et al.Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer's disease:integrating molecular analytical methods,pharmacokinetic and clinical data[J].CNS drugs,2017,31(6):495-509.
[22]Dasilva K A,Brown M E,Cousins J E,et al.scyllo-inositol(EL-ND005)ameliorates amyloid pathology in an aggressive mouse model ofAlzheimer's disease[J].Alzheimer's&Dementia:The Journal of the Alzheimer's Association,2009,5(4):425.
[23]Chauhan V,Ji L,Chauhan A.Anti-amyloidogenic,anti-oxidant and anti-apoptotic role of gelsolin in Alzheimer's disease[J].Biogerontology,2008,9(6):381-389.
[24]Luc Buée,Thierry Bussière,Valérie Buée-Scherrer,et al.Buée L,Bussière T,Buée-Scherrer V,Delacourte A,Hof PR.Tau protein isoforms,phosphorylation and role in neurodegenerative disorders[J].Brain Research Reviews,2000,33(1):95-130.
[25]West S,Bhugra P.Emerging drug targets for Aβand tau in Alzheimer's disease:a systematic review[J].British journal of clinical pharmacology,2015,80(2):221-234.
[26]Garcia M L,Cleveland D W.Going new places using an old MAP:tau,microtubules and human neurodegenerative disease[J].Current opinion in cell biology,2001,13(1):41-48.
[27]Katja Hochgr fe,Sydow A,Matenia D,et al.Preventive methylene blue treatment preserves cognition in mice expressing fulllength pro-aggregant human Tau[J].Acta neuropathologica communications,2015,3(1):25.
[28]Ponce-Lopez T,Hong E,Abascal-D AZ M,et al.Role of GSK3βand PP2A on regulation of Tau phosphorylation in hippocampusandmemoryimpairmentinICV-STZanimalmodelofAlzheimer's disease[J].Advances in Alzheimer's Disease,2017,6(1):13.
[29]Engel T,Paloma Go i-Oliver,JoséJ.Lucas,et al.Chronic lithium administration to FTDP 17 tau and GSK 3βoverexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation,but pre formed neurofibrillary tangles do not revert[J]Journal of neurochemistry,2006,99(6):1445-1455.
[30]Shemesh E,Rudich A,Harman-Boehm I,et al.Effect of intranasal insulin on cognitive function:a systematic review[J].The Journal of Clinical Endocrinology&Metabolism,2012,97(2):366-376.
[31]Anand R,Gill K D,Mahdi A A.Therapeutics of Alzheimer's disease:Past,present and future[J].Neuropharmacology,2014,76(PA):27-50.
[32]Gourmaud S,Paquet C,Dumurgier J,et al.Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology:links to cognitive decline[J].Journal of psychiatry&neuroscience:JPN,2015,40(3):151.
[33]Zhou Q,Wang M,Du Y,et al.Inhibition of c Jun N terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice[J].Annals of neurology,2015,77(4):637-654.
[34]Corcoran N M,Martin D,Hutter-Paier B,et al.Sodium selenate specifically activates PP2A phosphatase,dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model[J].Journal of Clinical Neuroscience,2010,17(8):1025-1033.
[35]Dickey C A,Kamal A,Lundgren K,et al.The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins[J].The Journal of clinical investigation2007,117(3):648-658.
[36]Ma Q-L,Zuo X,Yang F,et al.Curcumin suppresses soluble tau dimers and corrects molecular chaperone,synaptic,and behavioral deficits in aged human tau transgenic mice[J].Journal of Biological Chemistry,2013,288(6):4056-4065.
[37]Serafini M M,Catanzaro M,Rosini M,et al.Curcumin in Alzheimer's disease:Can we think to new strategies and perspectives for this molecule?[J].Pharmacological research,2017,124:146-155.
[38]Zhang B,Maiti A,Shively S,et al.Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model[J].Proceedingsüa n~of the National Academy of Sciences of the United States of America,2005,102(1):227-231.
[39]Monacelli F,Cea M,Borghi R,et al.Do cancer drugs counteract neurodegeneration?Repurposing for alzheimer's disease[J].Journal of Alzheimer's Disease,2017,55(4):1295-1306.
[40]Brunden K R,Zhang B,Carroll J,et al.Epothilone D improves microtubule density,axonal integrity,and cognition in a transgenic mouse model of tauopathy[J].Journal of Neuroscience,2010,30(41):13861-13866.
[41]Matsuoka Y,Jouroukhin Y,Gray A J,et al.A neuronal microtubule-interacting agent,NAPVSIPQ,reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer's disease[J].Journal of Pharmacology and Experimental Therapeutics,2008,325(1):146-153.
[42]Moreira P,Cardoso S,Santos M,et al.The key role of mitochondria in Alzheimer's disease[J].Journal of Alzheimer's Disease,2006,9(2):101-110.
[43]Moreira P I,Santos M S,Oliveira C R.Alzheimer's disease:a lesson from mitochondrial dysfunction[J].Antioxidants&redox signaling,2007,9(10):1621-1630.
[44]Cottrell D,Borthwick G,Johnson M,et al.The role of cytochrome c oxidase deficient hippocampal neurones in Alzheimer's disease[J].Neuropathology and applied neurobiology,2002,28(5):390-396.
[45]Lee J,Boo J H,Ryu H.The failure of mitochondria leads to neurodegeneration:Do mitochondria need a jump start?[J].Advanced drug delivery reviews,2009,61(14):1316-1323.
[46]Tauskela J S.MitoQ-a mitochondria-targeted antioxidant[J].IDrugs:the investigational drugs journal,2007,10(6):399-412.
[47]Smith R A,Adlam V J,Blaikie F H,et al.Mitochondria targeted antioxidants in the treatment of disease[J].Annals of the New York Academy of Sciences,2008,1147(1):105-111.
[48]Manczak M,Mao P,Calkins M J,et al.Mitochondria-targeted antioxidants protect against amyloid-βtoxicity in Alzheimer's disease neurons[J].Journal of Alzheimer's Disease,2010,20(s2):S609-S631.
[49]Ba I T V,Ruitenberg A,Hofman A,et al.Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease[J].New England Journal of Medicine,2001,345(21):1515-1521.
[50]Deardorff W J,Grossberg G T.Targeting neuroinflammation in Alzheimer's disease:evidence for NSAIDs and novel therapeutics[J].Expert review of neurotherapeutics,2017,17(1):17-32.
[51]Weggen S,Eriksen J L,Das P,et al.A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity[J].Nature,2001,414(6860):212.