异常神经元细胞周期再进入：阿尔茨海默病和大脑胰岛素抵抗的病理汇合及其与癌症的关系。
Aberrant Neuronal Cell Cycle Re-Entry: The Pathological Confluence of Alzheimer's Disease and Brain Insulin Resistance, and Its Relation to Cancer.
机构信息
Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
Department of Biology, University of Virginia, Charlottesville, VA, USA.
出版信息
J Alzheimers Dis. 2019;67(1):1-11. doi: 10.3233/JAD-180874.
Abstract
Aberrant neuronal cell cycle re-entry (CCR) is a phenomenon that precedes and may mechanistically lead to a majority of the neuronal loss observed in Alzheimer's disease (AD). Recent developments concerning the regulation of aberrant neuronal CCR in AD suggest that there are potential intracellular signaling "hotspots" in AD, cancer, and brain insulin resistance, the latter of which is characteristically associated with AD. Critically, these common signaling nodes across different human diseases may represent currently untapped therapeutic opportunities for AD. Specifically, repurposing of existing US Food and Drug Administration-approved pharmacological agents, including experimental therapeutics that target the cell cycle in cancer, may be an innovative avenue for future AD-directed drug discovery and development. In this review we discuss overlapping aspects of AD, cancer, and brain insulin resistance from the perspective of neuronal CCR, and consider strategies to exploit them for prevention or therapeutic intervention of AD.
摘要
异常的神经元细胞周期再进入（CCR）是一种先于并可能在机制上导致阿尔茨海默病（AD）中观察到的大多数神经元丢失的现象。最近关于 AD 中异常神经元 CCR 的调节的研究进展表明，AD、癌症和大脑胰岛素抵抗中存在潜在的细胞内信号“热点”，后者与 AD 密切相关。关键的是，这些不同人类疾病之间的共同信号节点可能代表着目前针对 AD 尚未开发的治疗机会。具体来说，重新利用现有的美国食品和药物管理局批准的药理学制剂，包括针对癌症细胞周期的实验性治疗药物，可能是未来针对 AD 的药物发现和开发的创新途径。在这篇综述中，我们从神经元 CCR 的角度讨论了 AD、癌症和大脑胰岛素抵抗的重叠方面，并考虑了利用这些方面预防或治疗 AD 的策略。
相似文献
1
Aberrant Neuronal Cell Cycle Re-Entry: The Pathological Confluence of Alzheimer's Disease and Brain Insulin Resistance, and Its Relation to Cancer.异常神经元细胞周期再进入：阿尔茨海默病和大脑胰岛素抵抗的病理汇合及其与癌症的关系。
J Alzheimers Dis. 2019;67(1):1-11. doi: 10.3233/JAD-180874.
2
Distinct chronology of neuronal cell cycle re-entry and tau pathology in the 3xTg-AD mouse model and Alzheimer's disease patients.3xTg-AD小鼠模型和阿尔茨海默病患者中神经元细胞周期重新进入与tau病理的不同时间顺序。
J Alzheimers Dis. 2015;43(1):57-65. doi: 10.3233/JAD-141083.
3
Neuronal Cell Cycle Re-Entry Enhances Neuropathological Features in AppNLF Knock-In Mice.神经元细胞周期再进入增强 APPNLF 敲入小鼠的神经病理学特征。
J Alzheimers Dis. 2021;82(4):1683-1702. doi: 10.3233/JAD-210091.
4
Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes.外周胰岛素增敏药物二甲双胍改善神经元胰岛素抵抗和阿尔茨海默病样改变。
Neuropharmacology. 2011 May;60(6):910-20. doi: 10.1016/j.neuropharm.2011.01.033. Epub 2011 Jan 26.
5
Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer's disease.脂联素模拟新型九肽可挽救阿尔茨海默病中异常的神经元代谢相关记忆缺陷。
Mol Neurodegener. 2021 Apr 13;16(1):23. doi: 10.1186/s13024-021-00445-4.
6
Cell cycle re-entry in Alzheimer's disease: a major neuropathological characteristic?阿尔茨海默病中的细胞周期重新进入：一个主要的神经病理学特征？
Curr Alzheimer Res. 2009 Jun;6(3):205-12. doi: 10.2174/156720509788486590.
7
Pathological implications of cell cycle re-entry in Alzheimer disease.阿尔茨海默病中细胞周期再进入的病理意义。
Expert Rev Mol Med. 2010 Jun 29;12:e19. doi: 10.1017/S146239941000150X.
8
A reevaluation of tetraploidy in the Alzheimer's disease brain.对阿尔茨海默病大脑中四倍体的再评估。
Neurodegener Dis. 2009;6(5-6):221-9. doi: 10.1159/000236901. Epub 2009 Sep 9.
9
N-methyl-D-aspartate receptor-mediated calcium influx connects amyloid-β oligomers to ectopic neuronal cell cycle reentry in Alzheimer's disease.N-甲基-D-天冬氨酸受体介导的钙内流将淀粉样β寡聚物与阿尔茨海默病中的神经元细胞周期异位重新进入连接起来。
Alzheimers Dement. 2018 Oct;14(10):1302-1312. doi: 10.1016/j.jalz.2018.05.017. Epub 2018 Jul 4.
10
A Unified Hypothesis of Early- and Late-Onset Alzheimer's Disease Pathogenesis.早发性和晚发性阿尔茨海默病发病机制的统一假说
J Alzheimers Dis. 2015;47(1):33-47. doi: 10.3233/JAD-143210.
引用本文的文献
1
Implications of Krüppel-like factor signaling in neuroinflammation for neurodegenerative diseases.Krüppel样因子信号在神经炎症中对神经退行性疾病的影响。
Am J Transl Res. 2025 Apr 15;17(4):3009-3030. doi: 10.62347/MIHM9413. eCollection 2025.
2
Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration.神经退行性变中TDP - 43磷酸化的分子机制及后果
Mol Neurodegener. 2025 May 8;20(1):53. doi: 10.1186/s13024-025-00839-8.
3
Prime Editing in Dividing and Quiescent Cells.分裂细胞和静止细胞中的碱基编辑
Int J Mol Sci. 2025 Apr 11;26(8):3596. doi: 10.3390/ijms26083596.
4
Systems-Level Interactome Mapping Reveals Actionable Protein Network Dysregulation Across the Alzheimer's Disease Spectrum.系统水平的相互作用组图谱揭示了阿尔茨海默病谱系中可操作的蛋白质网络失调。
Res Sq. 2025 Feb 12:rs.3.rs-5930673. doi: 10.21203/rs.3.rs-5930673/v1.
5
Brain Plasticity and Cell Competition: Immediate Early Genes Are the Focus.脑可塑性与细胞竞争：即刻早期基因是关键
Cells. 2025 Jan 19;14(2):143. doi: 10.3390/cells14020143.
6
Effects of Pterostilbene on the Cell Division Cycle of a Neuroblastoma Cell Line.紫檀芪对神经母细胞瘤细胞系细胞分裂周期的影响。
Nutrients. 2024 Nov 29;16(23):4152. doi: 10.3390/nu16234152.
7
Integrative pathway analysis across humans and 3D cellular models identifies the p38 MAPK-MK2 axis as a therapeutic target for Alzheimer's disease.跨人类和3D细胞模型的综合通路分析确定p38丝裂原活化蛋白激酶-MK2轴为阿尔茨海默病的治疗靶点。
Neuron. 2025 Jan 22;113(2):205-224.e8. doi: 10.1016/j.neuron.2024.10.029. Epub 2024 Nov 27.
8
New insights on the link between Epstein‑Barr virus infection and cognitive decline in neurodegenerative diseases (Review).爱泼斯坦-巴尔病毒感染与神经退行性疾病认知衰退之间联系的新见解（综述）
Exp Ther Med. 2024 Aug 30;28(5):413. doi: 10.3892/etm.2024.12702. eCollection 2024 Nov.
9
Polysaccharides from Protect Post-Mitotic Neurons against Cell Cycle Re-Entry and Apoptosis Induced by the Amyloid-Beta Peptide by Blocking Sonic Hedgehog Expression.从多糖保护有丝分裂后神经元免受淀粉样β肽诱导的细胞周期再进入和细胞凋亡，通过阻断 Sonic Hedgehog 表达。
Int J Mol Sci. 2024 Jul 3;25(13):7316. doi: 10.3390/ijms25137316.
10
Altered glia-neuron communication in Alzheimer's Disease affects WNT, p53, and NFkB Signaling determined by snRNA-seq.阿尔茨海默病中神经胶质细胞-神经元通讯的改变通过 snRNA-seq 影响 WNT、p53 和 NFkB 信号通路。
Cell Commun Signal. 2024 Jun 7;22(1):317. doi: 10.1186/s12964-024-01686-8.
本文引用的文献
1
A novel lysosome-to-mitochondria signaling pathway disrupted by amyloid-β oligomers.淀粉样β寡聚体破坏的新型溶酶体到线粒体信号通路。
EMBO J. 2018 Nov 15;37(22). doi: 10.15252/embj.2018100241. Epub 2018 Oct 22.
2
N-methyl-D-aspartate receptor-mediated calcium influx connects amyloid-β oligomers to ectopic neuronal cell cycle reentry in Alzheimer's disease.N-甲基-D-天冬氨酸受体介导的钙内流将淀粉样β寡聚物与阿尔茨海默病中的神经元细胞周期异位重新进入连接起来。
Alzheimers Dement. 2018 Oct;14(10):1302-1312. doi: 10.1016/j.jalz.2018.05.017. Epub 2018 Jul 4.
3
BACE failures lower AD expectations, again.β-分泌酶（BACE）研发失败再次降低了人们对阿尔茨海默病（AD）治疗的期望。
Nat Rev Drug Discov. 2018 May 30;17(6):385. doi: 10.1038/nrd.2018.94.
4
Old Drugs as New Treatments for Neurodegenerative Diseases.老药作为神经退行性疾病的新疗法
Pharmaceuticals (Basel). 2018 May 11;11(2):44. doi: 10.3390/ph11020044.
5
CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought.CDK4/6 抑制剂：作用机制可能不像以前认为的那么简单。
Cancer Cell. 2018 Jul 9;34(1):9-20. doi: 10.1016/j.ccell.2018.03.023. Epub 2018 May 3.
6
Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence.细胞周期异质性决定了神经干细胞从静止状态激活的时间。
Science. 2018 Apr 6;360(6384):99-102. doi: 10.1126/science.aan8795.
7
Oncogene-induced senescence: a double edged sword in cancer.癌基因诱导的衰老：癌症的双刃剑。
Acta Pharmacol Sin. 2018 Oct;39(10):1553-1558. doi: 10.1038/aps.2017.198. Epub 2018 Apr 5.
8
Targeting the PI3K pathway in cancer: are we making headway?针对癌症中的 PI3K 通路：我们是否取得进展？
Nat Rev Clin Oncol. 2018 May;15(5):273-291. doi: 10.1038/nrclinonc.2018.28. Epub 2018 Mar 6.
9
The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease.利拉鲁肽（糖尿病药物）可逆转小鼠的认知障碍，并减轻阿尔茨海默病非人灵长类动物模型中的胰岛素受体和突触病理。
J Pathol. 2018 May;245(1):85-100. doi: 10.1002/path.5056. Epub 2018 Apr 2.
10
Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums.2 型糖尿病和阿尔茨海默病中的脑胰岛素抵抗：概念与难题。
Nat Rev Neurol. 2018 Mar;14(3):168-181. doi: 10.1038/nrneurol.2017.185. Epub 2018 Jan 29.
Zotero 插件