Rho/ROCK信号通路在阿尔茨海默病中的研究进展
|
摘要
阿尔茨海默病(Alzheimer's disease,AD)是导致痴呆最常见的病因,随着人口的老龄化,患AD的人数逐年攀升,目前尚无有效的治疗方法。AD的发病机制尚未完全明了,目前认为其是一种多因素参与的疾病,其病理特征主要是β淀粉样蛋白(β-amyloid protein,Aβ)的沉积和神经纤维素的缠结(neurofibrillary tangles,NFT)。目前认为减少Aβ的产生能延缓或者预防AD的发展,而Rho/ROCK信号通路参与此病理过程,故Rho/ROCK抑制剂成为了AD治疗研究的新靶点。他汀类药物能抑制Rho/ROCK信号通路,为AD的治疗提供了新的思路,现将就AD、Rho/ROCK信号通路及他汀类药物之间的关系展开综述。
Alzheimer's disease(AD) is the most common cause of dementia. As the population ages, the number of people with AD increases year by year. There is currently no effective treatment. The pathogenesis of AD has not been fully understood. It is currently considered to be a multifactorial disease. Its pathological features are mainly the deposition of beta-amyloid protein(Aβ) and the neurofibrillary tangles(NFT). At present, it is believed that reducing the production of Aβ can delay or prevent the development of AD. Rho/ROCK signaling pathway is involved in this pathological process, so Rho/ROCK inhibitors have become a new target for AD treatment research. Statins can inhibit Rho/ROCK signaling pathway, which provide new ideas for the treatment of AD. This review will summarize the relationship between AD, Rho/ROCK signaling pathway and statins.
Alzheimer's disease(AD) is the most common cause of dementia. As the population ages, the number of people with AD increases year by year. There is currently no effective treatment. The pathogenesis of AD has not been fully understood. It is currently considered to be a multifactorial disease. Its pathological features are mainly the deposition of beta-amyloid protein(Aβ) and the neurofibrillary tangles(NFT). At present, it is believed that reducing the production of Aβ can delay or prevent the development of AD. Rho/ROCK signaling pathway is involved in this pathological process, so Rho/ROCK inhibitors have become a new target for AD treatment research. Statins can inhibit Rho/ROCK signaling pathway, which provide new ideas for the treatment of AD. This review will summarize the relationship between AD, Rho/ROCK signaling pathway and statins.
引文
[1] LANE CA, HARDY J, SCHOTT JM, et al. Alzheimer's disease[J].Eur J Neurol, 2018, 25(1):59-70.
[2] RIDGE PG, HOYT KB, BOEHME K, et al. Assessment of the genetic variance of late-onset Alzheimer's disease[J]. Neurobiology of Aging, 2016, 41:200.e13-200.e20.
[3] KHALIL RB, KHOURY E AND KOUSSA S. Linking multiple pathogenic pathways in Alzheimer's disease[J]. World Journal of Psychiatry, 2016, 6(2):208-214.
[4] KOZLOV S, AFONIN A, EVSYUKOV L, et al. Alzheimer's disease:as it was in the beginning[J]. Reviews in the Neurosciences, 2017. 28(8):825-843.
[5] STANKIEWICZ TR, LINSEMAN DA. Rho family GTPases:key players in neuronal development, neuronal survival, and neurodegeneration[J]. Frontiers in cellular neuroscience, 2014, 8:314-327.
[6] LAI AY, MCLAURIN J. Rho-associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease[J]. Journal of Neurochemistry, 2018, 144(5):659-668.
[7] SHIMOKAWA H, SUNAMURA S, SATOH K. RhoA/Rho-Kinase in the Cardiovascular System[J]. Circulation Research, 2016, 118(2):352-366.
[8] HENSEL N, RADEMACHER S, CLAUS P. Chatting with the neighbors:crosstalk between Rho-kinase(ROCK)and other signaling pathways for treatment of neurological disorders[J]. Frontiers in Neuroscience, 2015, 9:198-227.
[9] NAKAYAMA AY, HARMS MB, LUO L. Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons[J]. Neurosci, 2000, 20(14):5329-5338.
[10]万君,李余星,郑卫红,等.γ-分泌酶的空间结构及调节剂的研究进展[J].中国药理学与毒理学杂志, 2015, 29(6):979-985.
[11] SAMBAMURTI K, GREIG NH, UTSUKI T, et al. Targets for AD treatment:conflicting messages fromγ-secretase inhibitors[J]. Journal of Neurochemistry, 2011, 117(3):359-374.
[12] HERSKOWITZ JH, FENG Y, MATTHEYSES AL, et al. Pharmacologic Inhibition of ROCK2 Suppresses Amyloid-βProduction in an alzheimer's disease mouse model[J]. Journal of Neuroscience, 2013,33(49):19086-19098.
[13] ZHOU Y, SU Y, LI B, et al. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho[J]. Science,2003, 302(5648):1215-1217.
[14] SCHULTZ BG, PATTEN DK, BERLAU DJ. The role of statins in both cognitive impairment and protection against dementia:a tale of two mechanisms[J]. Transl Neurodegener, 2018, 7:5.
[15] FORCE USPST. Statin use for the primary prevention of cardiovascular disease in adults:US preventive services task force recommendation statement[J]. J Am Med Assoc, 2016, 316:1997-2007.
[16] OSTROWSKI SM, JOHNSON K, SIEFERT M, et al. Simvastatin inhibits protein isoprenylation in the brain[J]. Neuroscience, 2016,329:264-274.
[17] JEONG A, SUAZO KF, WOOD WG, et al. Isoprenoids and protein prenylation:implications in the pathogenesis and therapeutic intervention of Alzheimer's disease[J]. Crit Rev Biochem Mol Biol,2018, 53(3):279-310.
[18]付婕琴,刘海洋,胡昌华.他汀类药物治疗阿尔茨海默病的非降脂作用新机制[J].中国药学杂志, 2010, 45(11):804-807.
[19] FOLCH J, PETROV D, ETTCHETO M, et al. Current research therapeutic strategies for Alzheimer's disease treatment[J]. Neural Plast,2016, 2016:1-15.
[20] CHONG C, AI N, LEE SM. ROCK in CNS:different roles of isoforms and therapeutic target for neurodegenerative disorders[J]. Current drug targets, 2017, 18(4):455-462.
[21] HOTTMAN DA, LI L. Protein prenylation and synaptic plasticity:implications for Alzheimer's disease[J]. Molecular Neurobiology,2014, 50(1):177-185.
[2] RIDGE PG, HOYT KB, BOEHME K, et al. Assessment of the genetic variance of late-onset Alzheimer's disease[J]. Neurobiology of Aging, 2016, 41:200.e13-200.e20.
[3] KHALIL RB, KHOURY E AND KOUSSA S. Linking multiple pathogenic pathways in Alzheimer's disease[J]. World Journal of Psychiatry, 2016, 6(2):208-214.
[4] KOZLOV S, AFONIN A, EVSYUKOV L, et al. Alzheimer's disease:as it was in the beginning[J]. Reviews in the Neurosciences, 2017. 28(8):825-843.
[5] STANKIEWICZ TR, LINSEMAN DA. Rho family GTPases:key players in neuronal development, neuronal survival, and neurodegeneration[J]. Frontiers in cellular neuroscience, 2014, 8:314-327.
[6] LAI AY, MCLAURIN J. Rho-associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease[J]. Journal of Neurochemistry, 2018, 144(5):659-668.
[7] SHIMOKAWA H, SUNAMURA S, SATOH K. RhoA/Rho-Kinase in the Cardiovascular System[J]. Circulation Research, 2016, 118(2):352-366.
[8] HENSEL N, RADEMACHER S, CLAUS P. Chatting with the neighbors:crosstalk between Rho-kinase(ROCK)and other signaling pathways for treatment of neurological disorders[J]. Frontiers in Neuroscience, 2015, 9:198-227.
[9] NAKAYAMA AY, HARMS MB, LUO L. Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons[J]. Neurosci, 2000, 20(14):5329-5338.
[10]万君,李余星,郑卫红,等.γ-分泌酶的空间结构及调节剂的研究进展[J].中国药理学与毒理学杂志, 2015, 29(6):979-985.
[11] SAMBAMURTI K, GREIG NH, UTSUKI T, et al. Targets for AD treatment:conflicting messages fromγ-secretase inhibitors[J]. Journal of Neurochemistry, 2011, 117(3):359-374.
[12] HERSKOWITZ JH, FENG Y, MATTHEYSES AL, et al. Pharmacologic Inhibition of ROCK2 Suppresses Amyloid-βProduction in an alzheimer's disease mouse model[J]. Journal of Neuroscience, 2013,33(49):19086-19098.
[13] ZHOU Y, SU Y, LI B, et al. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho[J]. Science,2003, 302(5648):1215-1217.
[14] SCHULTZ BG, PATTEN DK, BERLAU DJ. The role of statins in both cognitive impairment and protection against dementia:a tale of two mechanisms[J]. Transl Neurodegener, 2018, 7:5.
[15] FORCE USPST. Statin use for the primary prevention of cardiovascular disease in adults:US preventive services task force recommendation statement[J]. J Am Med Assoc, 2016, 316:1997-2007.
[16] OSTROWSKI SM, JOHNSON K, SIEFERT M, et al. Simvastatin inhibits protein isoprenylation in the brain[J]. Neuroscience, 2016,329:264-274.
[17] JEONG A, SUAZO KF, WOOD WG, et al. Isoprenoids and protein prenylation:implications in the pathogenesis and therapeutic intervention of Alzheimer's disease[J]. Crit Rev Biochem Mol Biol,2018, 53(3):279-310.
[18]付婕琴,刘海洋,胡昌华.他汀类药物治疗阿尔茨海默病的非降脂作用新机制[J].中国药学杂志, 2010, 45(11):804-807.
[19] FOLCH J, PETROV D, ETTCHETO M, et al. Current research therapeutic strategies for Alzheimer's disease treatment[J]. Neural Plast,2016, 2016:1-15.
[20] CHONG C, AI N, LEE SM. ROCK in CNS:different roles of isoforms and therapeutic target for neurodegenerative disorders[J]. Current drug targets, 2017, 18(4):455-462.
[21] HOTTMAN DA, LI L. Protein prenylation and synaptic plasticity:implications for Alzheimer's disease[J]. Molecular Neurobiology,2014, 50(1):177-185.