Research Progress on the Relationship between the Apolipoprotein E Gene and Brain Injury after Ischemic Stroke

doi:10.3969/j.issn.1673-5765.2026.05.007

Abstract

Abstract: The apolipoprotein E (APOE) gene and its encoded protein ApoE represent promising targets worthy of attention in studies of brain cytoprotection for ischemic stroke. The ApoE protein is involved in pathophysiological processes closely linked to tissue injury and repair after cerebral ischemia, including cerebral lipid transport, glia-neuron support, regulation of inflammatory responses, and maintenance of the neurovascular unit and the blood-brain barrier homeostasis. Preclinical studies have demonstrated that endogenous ApoE deficiency in Apoe gene knockout mice aggravates experimental ischemic brain injury. Humanized APOE2, APOE3, and APOE4 knock-in mouse models further indicate that mice expressing the human ApoE4 protein isoform may develop more severe cerebral infarction and neurological deficits. In addition, interventional studies have verified that ApoE mimetic peptides CN-105 and COG1410 exert effects of regulating inflammatory responses, stabilizing the blood-brain barrier, and improving neurological function in animal models of ischemic stroke. Clinical studies have yielded inconsistent findings regarding the associations between APOE genotype and ischemic stroke risk, age at onset, short-term functional outcomes, and post-stroke cognitive outcomes. Current evidence is insufficient to support APOE genotype as an independent predictive biomarker or a well-established therapeutic target for ischemic stroke. This review summarizes the potential mechanisms, preclinical and clinical research evidence regarding the APOE gene and ApoE protein-related pathways in post-ischemic brain injury, as well as therapeutic strategies targeting ApoE-associated pathways.

Key words: Ischemic stroke; Apolipoprotein E; Gene; Protein; Brain cytoprotection

摘要： 载脂蛋白E（apolipoprotein E，APOE）基因及其编码蛋白ApoE是缺血性卒中脑细胞保护研究中值得关注的靶点。ApoE蛋白参与体内脂质转运、胶质细胞和神经元支持、炎症反应调节，以及神经血管单元和血脑屏障稳态维持等与脑组织损伤和修复密切相关的病理生理过程。临床前实验提示，Apoe基因缺失小鼠模型中，内源性ApoE蛋白缺乏可加重缺血性脑损伤；在人源化APOE2、APOE3和APOE4基因敲入小鼠模型中，表达人类ApoE4蛋白亚型的小鼠具有更严重的脑梗死和神经功能缺损表现。另外，干预性实验证明，ApoE模拟肽CN-105和COG1410在缺血性卒中动物模型中具有调节炎症反应、维持血脑屏障稳定性及改善神经功能的作用。临床研究显示，APOE基因型与缺血性卒中的发生风险、发病年龄、短期功能结局及卒中后认知结局的关系尚无统一结论。APOE基因目前尚不足以成为缺血性卒中的独立预测指标或成熟的干预靶点。本文围绕APOE基因及ApoE蛋白相关通路在缺血性卒中后脑损伤中的作用，综述其可能机制、临床前实验和临床研究证据，以及针对该通路的治疗探索。

关键词: 缺血性卒中; 载脂蛋白E; 基因; 蛋白; 脑细胞保护

CLC Number:

CHANG-CAO Wenjing, XU Shuhong, LI Jian, LI Shuya. Research Progress on the Relationship between the Apolipoprotein E Gene and Brain Injury after Ischemic Stroke [J]. Chinese Journal of Stroke, 2026, 21(5): 570-576.

常曹文静, 许淑红, 李俭, 李姝雅. 载脂蛋白E基因与缺血性卒中后脑损伤关系的研究进展[J]. 中国卒中杂志, 2026, 21(5): 570-576.

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URL: https://www.chinastroke.org.cn/EN/10.3969/j.issn.1673-5765.2026.05.007

https://www.chinastroke.org.cn/EN/Y2026/V21/I5/570

References

[1] CHAMORRO A，DIRNAGL U，URRA X，et al. Neuroprotection in acute stroke：targeting excitotoxicity，oxidative and nitrosative stress，and inflammation[J]. Lancet Neurol，2016，15（8）：869-881.
[2] GHOZY S，REDA A，VARNEY J，et al. Neuroprotection in acute ischemic stroke：a battle against the biology of nature[J/OL]. Front Neurol，2022，13：870141[2026-03-08]. https://doi.org/10.3389/fneur.2022.870141.
[3] WINDHAM I A，COHEN S. The cell biology of ApoE in the brain[J]. Trends Cell Biol，2024，34（4）：338-348.
[4] JAMES M L，KOMISAROW J M，WANG H C，et al. Therapeutic development of apolipoprotein E mimetics for acute brain injury：augmenting endogenous responses to reduce secondary injury[J]. Neurotherapeutics，2020，17（2）：475-483.
[5] HOLTZMAN D M，HERZ J，BU G J. Apolipoprotein E and apolipoprotein E receptors：normal biology and roles in Alzheimer disease[J/OL]. Cold Spring Harb Perspect Med，2012，2（3）：a006312[2026-03-08]. https://doi.org/10.1101/cshperspect.a006312.
[6] HUANG Y D，MAHLEY R W. Apolipoprotein E：structure and function in lipid metabolism，neurobiology，and Alzheimer’s diseases[J/OL]. Neurobiol Dis，2014，72（Pt A）：3-12[2026-03-08]. https://doi.org/10.1016/j.nbd.2014.08.025.
[7] MAHLEY R W. Central nervous system lipoproteins：ApoE and regulation of cholesterol metabolism[J]. Arterioscler Thromb Vasc Biol，2016，36（7）：1305-1315.
[8] KLOSKE C M，WILCOCK D M. The important interface between apolipoprotein E and neuroinflammation in Alzheimer’s disease[J/OL]. Front Immunol，2020，11：754[2026-03-08]. https://doi.org/10.3389/fimmu.2020.00754.
[9] RHEA E M，BANKS W A. Interactions of lipids，lipoproteins，and apolipoproteins with the blood-brain barrier[J]. Pharm Res，2021，38（9）：1469-1475.
[10] ZLOKOVIC B V. Cerebrovascular effects of apolipoprotein E：implications for Alzheimer disease[J]. JAMA Neurol，2013，70（4）：440-444.
[11] WAHRLE S E，JIANG H，PARSADANIAN M，et al. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted ApoE[J]. J Biol Chem，2004，279（39）：40987-40993.
[12] LASKOWITZ D T，SHENG H，BART R D，et al. Apolipoprotein E-deficient mice have increased susceptibility to focal cerebral ischemia[J]. J Cereb Blood Flow Metab，1997，17（7）：753-758.
[13] SHENG H，LASKOWITZ D T，MACKENSEN G B，et al. Apolipoprotein E deficiency worsens outcome from global cerebral ischemia in the mouse[J]. Stroke，1999，30（5）：1118-1124.
[14] HORSBURGH K，KELLY S，MCCULLOCH J，et al. Increased neuronal damage in apolipoprotein E-deficient mice following global ischaemia[J]. Neuroreport，1999，10（4）：837-841.
[15] MORI T，KOBAYASHI M，TOWN T，et al. Increased vulnerability to focal ischemic brain injury in human apolipoprotein E4 knock-in mice[J]. J Neuropathol Exp Neurol，2003，62（3）：280-291.
[16] DHUNGANA H，ROLOVA T，SAVCHENKO E，et al. Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele[J/OL]. J Neuroinflammation，2013，10（1）：102[2026-03-08]. https://doi.org/10.1186/1742-2094-10-102.
[17] TU T M，KOLLS B J，SODERBLOM E J，et al. Apolipoprotein E mimetic peptide，CN-105，improves outcomes in ischemic stroke[J]. Ann Clin Transl Neurol，2017，4（4）：246-265.
[18] XUE Y W，GU M H，CHEN C L，et al. Apolipoprotein E mimetic peptide COG1410 alleviates blood-brain barrier injury in a rat model of ischemic stroke[J/OL]. Mol Med Rep，2023，27（4）：85[2026-03-08]. https://doi.org/10.3892/mmr.2023.12972.
[19] SUDLOW C，MARTÍNEZ GONZÁLEZ N A，KIM J，et al. Does apolipoprotein E genotype influence the risk of ischemic stroke，intracerebral hemorrhage，or subarachnoid hemorrhage？Systematic review and meta-analyses of 31 studies among 5961 cases and 17 965 controls[J]. Stroke，2006，37（2）：364-370.
[20] KHAN T A，SHAH T，PRIETO D，et al. Apolipoprotein E genotype，cardiovascular biomarkers and risk of stroke：systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals[J]. Int J Epidemiol，2013，42（2）：475-492.
[21] QIAO S Y，SHANG K，CHU Y H，et al. Apolipoprotein E ε4 polymorphism as a risk factor for ischemic stroke：a systematic review and meta-analysis[J/OL]. Dis Markers，2022：1407183[2026-03-08]. https://doi.org/10.1155/2022/1407183.
[22] LAGGING C，LORENTZEN E，STANNE T M，et al. ApoE ε4 is associated with younger age at ischemic stroke onset but not with stroke outcome[J]. Neurology，2019，93（19）：849-853.
[23] MCCARRON M O，MUIR K W，NICOLL J A，et al. Prospective study of apolipoprotein E genotype and functional outcome following ischemic stroke[J]. Arch Neurol，2000，57（10）：1480-1484.
[24] ZHANG Y J，LIU S L，YUE W，et al. Association of apolipoprotein E genotype with outcome in hospitalized ischemic stroke patients[J/OL]. Medicine（Baltimore），2017，96（50）：e8964[2026-03-08]. https://doi.org/10.1097/MD.0000000000008964.
[25] PAN W，ZHANG M，GUO Z P，et al. Association between apolipoprotein E polymorphism and clinical outcome after ischemic stroke，intracerebral hemorrhage，and subarachnoid hemorrhage[J]. Cerebrovasc Dis，2022，51（3）：313-322.
[26] RONG X M，CHEN J J，PAN D，et al. Association between apolipoprotein E genotype and functional outcome in acute ischemic stroke[J]. Aging（Albany NY），2023，15（1）：108-118.
[27] RAJAN K B，AGGARWAL N T，SCHNEIDER J A，et al. Role of ApoE ε4 allele and incident stroke on cognitive decline and mortality[J]. Alzheimer Dis Assoc Disord，2016，30（4）：318-323.
[28] CHEN J H，CHAN L，HONG C T，et al. Role of apolipoprotein E（ApoE）ε4 in cognitive impairment after a stroke：a prospective cohort study[J]. Aging（Albany NY），2025，17（5）：1261-1274.
[29] PENDLEBURY S T，POOLE D，BURGESS A，et al. ApoE-ε4 genotype and dementia before and after transient ischemic attack and stroke：population-based cohort study[J]. Stroke，2020，51（3）：751-758.
[30] HOU Y B，HUA S Y，GUO Z，et al. ApoE ε2 is associated with reduced risk of early post-stroke cognitive impairment but not with long-term functional outcome[J/OL]. BMC Neurol，2025，25：363[2026-03-08]. https://doi.org/10.1186/s12883-025-04371-6.
[31] JAMES M L，TROY J，NOWACKI N，et al. CN-105 in participants with acute supratentorial intracerebral hemorrhage（CATCH）trial[J]. Neurocrit Care，2022，36（1）：216-225.
[32] GUPTILL J T，RAJA S M，BOAKYE-AGYEMAN F，et al. Phase Ⅰ randomized，double-blind，placebo-controlled study to determine the safety，tolerability，and pharmacokinetics of a single escalating dose and repeated doses of CN-105 in healthy adult subjects[J]. J Clin Pharmacol，2017，57（6）：770-776.
[33] SUTHERLAND B A，MINNERUP J，BALAMI J S，et al. Neuroprotection for ischaemic stroke：translation from the bench to the bedside[J]. Int J Stroke，2012，7（5）：407-418.
[34] XU S Y，PAN S Y. The failure of animal models of neuroprotection in acute ischemic stroke to translate to clinical efficacy[J/OL]. Med Sci Monit Basic Res，2013，19：37-45[2026-03-08]. https://doi.org/10.12659/MSMBR.883750.
[35] DHIR N，MEDHI B，PRAKASH A，et al. Pre-clinical to clinical translational failures and current status of clinical trials in stroke therapy：a brief review[J]. Curr Neuropharmacol，2020，18（7）：596-612.