坏死性凋亡在阿尔茨海默病中的分子机制与 治疗策略

陆志成  唐丽娜  莫圣龙  杨成敏  简崇东  商敬伟

doi:10.16098/j.issn.0529-1356.2025.02.015

PDF(851 KB)

解剖学报 ›› 2025, Vol. 56 ›› Issue (2) : 239-247. DOI: 10.16098/j.issn.0529-1356.2025.02.015

综述

坏死性凋亡在阿尔茨海默病中的分子机制与治疗策略

陆志成^{1, 2} 唐丽娜^{1, 2} 莫圣龙^{1, 2}杨成敏² 简崇东² 商敬伟^2*

作者信息 +

Molecular mechanism and therapeutic strategies of necrotic apoptosis in Alzheimer's disease

LU Zhi-cheng^1,2 TANG Li-na ^1,2 MO Sheng-long ^1,2 YANG Cheng-min² JIAN Chong-dong² SHANG Jing-wei ^2*
#br#

Author information +

文章历史 +

摘要

本综述深入探讨了坏死性凋亡在阿尔茨海默病（AD）中的关键作用，并以治疗策略、药物研发、前景与挑战等方面为基点，突出其在疾病发展中的重要性。首先，坏死性凋亡在AD的发病机制中扮演重要角色，特别是与β-淀粉样蛋白（Aβ）和Tau蛋白的异常代谢紧密相连。药物设计的主要焦点是调节这两种蛋白的代谢途径，以期减缓或抑制坏死性凋亡的进展。其次，药物研发方面取得的进展进一步凸显了坏死性凋亡在治疗AD中的重要性。当前的研究主要集中在影响Aβ和Tau蛋白代谢的药物上，例如仑卡奈单抗 (lecanemab) ，但面临着一些不一致的结果，强调对坏死性凋亡分子机制更全面的了解是必要的。最后，对AD中坏死性凋亡研究的前景与挑战进行了深入探讨。深入理解坏死性凋亡不仅有助于深化对AD病理机制的认识，也可能揭示新的治疗靶点。然而，面临多因素影响和治疗时机选择的挑战，需要未来更为深入的研究。综合而言，本综述呼吁，未来研究应更深入地理解坏死性凋亡的分子机制，加强治疗策略研究，深入了解其与其他细胞死亡途径的交叉调控，同时促进基础研究与临床实践之间的合作，推动对阿尔茨海默病和坏死性凋亡的全面理解和治疗手段的不断拓展。

Abstract

This review delves into the pivotal role of necrotic apoptosis in Alzheimer’s disease (AD), with a focus on treatment strategies, drug development, prospects, and challenges, highlighting its significance in the progression of the disease. Firstly, necrotic apoptosis plays a crucial role in the pathogenesis of AD, particularly in association with the abnormal metabolism of β-amyloid (Aβ) and Tau proteins. The primary focus of drug design is to regulate the metabolism pathways of these two proteins to slow down or inhibit the progression of necrotic apoptosis. Secondly, the progress in drug development further emphasizes the importance of necrotic apoptosis in treating AD. Current research mainly focuses on drugs that affect the metabolism of Aβ and Tau proteins, such as lecanemab. Still, inconsistent result underscore the necessity for a more comprehensive understanding of the molecular mechanisms of necrotic apoptosis. Finally, the prospects and challenges of necrotic apoptosis research in AD are thoroughly discussed. A deeper understanding of necrotic apoptosis contributes to a better comprehension of the pathological mechanisms of AD but also may reveal new therapeutic targets. However, challenges such as multifactorial influences and the selection of treatment timing necessitate further in-depth research in the future. In conclusion, this review advocates for future research to deepen the understanding of the molecular mechanisms of necrotic apoptosis, enhance research on treatment strategies, gain a deeper understanding of its cross-regulation with other cell death pathways, and promote collaboration between basic research and clinical practice to advance the comprehensive understanding and treatment of Alzheimer’s disease and necrotic apoptosis.

导出引用

陆志成唐丽娜莫圣龙杨成敏简崇东商敬伟. 坏死性凋亡在阿尔茨海默病中的分子机制与治疗策略[J]. 解剖学报. 2025, 56(2): 239-247 https://doi.org/10.16098/j.issn.0529-1356.2025.02.015

LU Zhi-cheng TANG Li-na MO Sheng-long YANG Cheng-min JIAN Chong-dong SHANG Jing-wei. Molecular mechanism and therapeutic strategies of necrotic apoptosis in Alzheimer's disease[J]. Acta Anatomica Sinica. 2025, 56(2): 239-247 https://doi.org/10.16098/j.issn.0529-1356.2025.02.015

中图分类号： R741.02

参考文献

［1］ Guzman-Martinez L, Calfío C, Farias GA, et al. New frontiers in the prevention, diagnosis, and treatment of Alzheimer’s disease［J］. J Alzheimer’s Dis, 2021, 82(s1): S51-S63.

［2］ Zhang DF, Xu M, Bi R, et al. Genetic analyses of Alzheimer’s disease in China: achievements and perspectives［J］. ACS Chem Neurosci, 2019, 10(2): 890-901.

［3］ Blennow K, Zetterberg H. Biomarkers for Alzheimer’s disease: current status and prospects for the future［J］. J Intern Med, 2018, 284(6): 643-663.

［4］ Liu X, Xie X, Ren Y, et al. The role of necroptosis in disease and treatment［J］. Med Comm, 2021, 2(4): 730-755.

［5］ Beretta GL, Zaffaroni N. Necroptosis and prostate cancer: molecular mechanisms and therapeutic potential［J］. Cells, 2022, 11(7): 1221.

［6］ Morgan MJ, Kim YS. Roles of RIPK3 in necroptosis, cell signaling, and disease［J］. Exp Mol Med, 2022, 54(10): 1695-1704.

［7］ Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death［J］. Nat Rev Mol Cell Biol, 2019, 21(2): 85-100.

［8］ Nguyen TT, Wei S, Nguyen TH, et al. Mitochondria-associated programmed cell death as a therapeutic target for age-related disease［J］. Exp Mol Med, 2023, 55(8): 1595-1619.

［9］ Goel P, Chakrabarti S, Goel K, et al. Neuronal cell death mechanisms in Alzheimer’s disease: an insight［J］. Front Mol Neurosci, 2022, 15: 937133.

［10］Seo J, Nam YW, Kim S, et al. Necroptosis molecular mechanisms: recent findings regarding novel necroptosis regulators［J］. Exp Mol Med, 2021, 53(6): 1007-1017.

［11］ Tonnus W, Meyer C, Paliege A, et al. The pathological features of regulated necrosis［J］. J Pathol, 2019, 247(5): 697-707.

［12］ Gong YN, Guy C, Olauson H, et al. ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences［J］. Cell, 2017, 169(2): 286-300.e16.

[13] Jaeschke H, Ramachandran A, Chao X, et al. Emerging and established modes of cell death during acetaminophen-induced liver injury［J］. Arch Toxicol, 2019, 93(12): 3491-3502.

［14］ Linkermann A, Green DR. Necroptosis［J］. N Engl J Med, 2014, 370(5): 455-465.

［15］ Berghe TV, Linkermann A, Jouan-Lanhouet S, et al. Regulated necrosis: the expanding network of non-apoptotic cell death pathways［J］. Nat Rev Mol Cell Biol, 2014, 15(2): 135-147.

［16］ Sahoo G, Samal D, Khandayataray P, et al. A review on caspases: key regulators of biological activities and apoptosis［J］. Mol Neurobiol, 2023, 60(10): 5805-5837.

［17］ Vandenabeele P, Galluzzi L, Vanden Berghe T, et al. Molecular mechanisms of necroptosis: an ordered cellular explosion［J］. Nat Rev Mol Cell Biol, 2010, 11(10): 700-714.

［18］ Yuan J, Ofengeim D. A guide to cell death pathways［J］. Nat Rev Mol Cell Biol, 2024, 25(5): 379-395.

［19］ Yeap HW, Chen KW. RIPK1 and RIPK3 in antibacterial defence［J］. Biochem Soc Trans, 2022, 50(6): 1583-1594.

［20］ Karlowitz R, van Wijk SJL. Surviving death: emerging concepts of RIPK3 and MLKL ubiquitination in the regulation of necroptosis［J］. FEBS J, 2021, 290(1): 37-54.

［21］ Liu S, Joshi K, Denning MF, et al. RIPK3 signaling and its role in the pathogenesis of cancers［J］. Cell Mol Life Sci, 2021, 78(23): 7199-7217.

［22］ Christgen S, Tweedell RE, Kanneganti TD. Programming inflammatory cell death for therapy［J］. Pharmacol Ther, 2022, 232: 108010.

［23］ Jiang Y, Chen X, Fan M, et al. TRAIL facilitates cytokine expression and macrophage migration during hypoxia/reoxygenation via ER stress-dependent NF-κB pathway［J］. Mol Immunol, 2017, 82: 123-136.

［24］ Newton K, Wickliffe KE, Dugger DL, et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis［J］. Nature, 2019, 574(7778): 428-431.

［25］ Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases［J］. Nat Rev Neurosci, 2018, 20(1): 19-33.

［26］ Zhu F, Zhang W, Yang T, et al. Complex roles of necroptosis in cancer［J］. J Zhejiang Univ-SCI B, 2019, 20(5): 399-413.

［27］ Raden Y, Shlomovitz I, Gerlic M. Necroptotic extracellular vesicles-present and future［J］. Semin Cell Dev Biol, 2021, 109: 106-113.

［28］ Riegman M, Sagie L, Galed C, et al. Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture［J］. Nat Cell Biol, 2020, 22(9): 1042-1048.

[29] Malireddi RK, Kesavardhana S, Kanneganti TD. ZBP1 and TAK1: master regulators of NLRP3 inflammasome/pyroptosis, apoptosis, and necroptosis (PAN-optosis) ［J］. Front Cell Infect Microbiol, 2019, 9: 406.

［30］ Yu Z, Jiang N, Su W, et al. Necroptosis: a novel pathway in neuroinflammation［J］. Front Pharmacol, 2021, 12: 701564.

［31］ Newton K. RIPK1 and RIPK3: critical regulators of inflammation and cell death［J］. Trends Cell Biol, 2015, 25(6): 347-353.

［32］ Tummers B, Green DR. Mechanisms of TNF-independent RIPK3-mediated cell death［J］. Biochem J, 2022, 479(19): 2049-2062.

［33］ Rius-Pérez S. P53 at the crossroad between mitochondrial reactive oxygen species and necroptosis［J］. Free Radic Biol Med, 2023, 207: 183-193.

［34］ Iurlaro R, Muñoz-Pinedo C. Cell death induced by endoplasmic reticulum stress［J］. FEBS J, 2015, 283(14): 2640-2652.

［35］ Nixon RA. Autophagy in neurodegenerative disease: friend, foe or turncoat ［J］ ? Trends Neurosci, 2006, 29(9): 528-535.

［36］ Belkhelfa M, Beder N, Mouhoub D, et al. The involvement of neuroinflammation and necroptosis in the hippocampus during vascular dementia［J］. J Neuroimmunol, 2018, 320: 48-57.

［37］ Wójcik P, Jastrzębski MK, Zięba A, et al. Caspases in Alzheimer’s disease: mechanism of activation, role, and potential treatment［J］. Mol Neurobiol, 2024,61(7): 4834-4853.

［38］ Cieri M, Vicario M, Vallese F, et al. Tau localises within mitochondrial sub-compartments and its caspase cleavage affects ER-mitochondria interactions and cellular Ca²⁺ handling［J］. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(10): 3247-3256.

［39］ Zhang R, Song Y, Su X, et al. Necroptosis and Alzheimer’s disease: pathogenic mechanisms and therapeutic opportunities［J］. J Alzheimer’s Dis, 2023, 94(s1): S367-S386.

［40］ Roberts JZ, Crawford N, Longley DB. The role of ubiquitination in apoptosis and necroptosis［J］. Cell Death Differ, 2021, 29(2): 272-284.

［41］ Moonen S, Koper MJ, Van Schoor E, et al. Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons［J］. Acta Neuropathol, 2022, 145(2): 175-195.

［42］ Fricker M, Tolkovsky AM, Borutaite V, et al. Neuronal cell death［J］. Physiol Rev, 2018, 98(2): 813-880.

［43］ Orobets KS, Karamyshev AL. Amyloid precursor protein and Alzheimer’s disease［J］. Int J Mol Sci, 2023, 24(19): 14794.

［44］ Choi SB, Kwon S, Kim JH, et al. The molecular mechanisms of neuroinflammation in Alzheimer’s disease, the consequence of neural cell death［J］. Int J Mol Sci, 2023, 24(14): 11757.

［45］ Olesen MA, Quintanilla RA. Pathological impact of tau proteolytical process on neuronal and mitochondrial function: a crucial role in Alzheimer’s disease［J］. Mol Neurobiol, 2023, 60(10): 5691-5707.

［46］ Ye K, Chen Z, Xu Y. The double-edged functions of necroptosis［J］. Cell Death Dis, 2023, 14(2): 163.

［47］ Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody［J］. Alzheimers Res Ther, 2021, 13(1): 80.

［48］ Panza F, Seripa D, Lozupone M, et al. The potential of solanezumab and gantenerumab to prevent Alzheimer’s disease in people with inherited mutations that cause its early onset［J］. Expert Opin Biol Ther, 2017, 18(1): 25-35.

［49］ Panza F, Imbimbo BP, Lozupone M, et al. Disease-modifying therapies for tauopathies: agents in the pipeline［J］. Expert Rev Neurother, 2019, 19(5): 397-408.

［50］ Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation［J］. Nature, 2015, 517(7534): 311-320.