{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:03:16Z","timestamp":1790701396381,"version":"4.1.0"},"reference-count":93,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Innovation Team of Shanxi Province","award":["202304051001039"],"award-info":[{"award-number":["202304051001039"]}]},{"name":"Shanxi Province Higher Education \u201cBillion Project\u201d Science and Technology Guidance Project","award":["BYJL023"],"award-info":[{"award-number":["BYJL023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Ischemic stroke is a leading cause of mortality and long-term disability worldwide, with complex pathophysiological mechanisms and limited therapeutic options. The identification of key molecular targets that can effectively modulate the multifaceted pathological and reparative processes underlying ischemic stroke is urgently needed. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor widely expressed in the central nervous system (CNS), where it regulates lipid and bioenergetic metabolism, preserves blood\u2012brain barrier (BBB) function, modulates synaptic signaling, and supports neural stem\/progenitor cell homeostasis. During cerebral ischemia, LRP1 undergoes a stage-dependent functional shift. In the acute phase, LRP1 promotes BBB disruption, tissue-type plasminogen activator (tPA)-associated hemorrhagic transformation, and early neuroinflammation, while also conferring neuroprotection by restraining inflammasome-mediated inflammatory responses and facilitating astrocyte-to-neuron mitochondrial transfer. In the recovery phase, LRP1 is involved in white matter injury and remodeling, including demyelination, remyelination, and white matter restoration. These effects are highly cell type\u2013specific, reflecting distinct functions of LRP1 in endothelial cells, astrocytes, microglia, neutrophils, and oligodendrocyte-lineage cells. This context-dependent complexity underscores the need for a systematic review of the role of LRP1 in stroke. Here, we summarize the structural features and physiological functions of LRP1 in the CNS, discuss its roles and underlying mechanisms in ischemic stroke, and highlight the therapeutic potential and challenges of LRP1-targeted strategies for stroke intervention.<\/jats:p>","DOI":"10.31083\/jin53774","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:16:31Z","timestamp":1790698591000},"source":"Crossref","is-referenced-by-count":0,"title":["LRP1 in Ischemic Stroke: From CNS Homeostasis to Ischemic Injury and Repair"],"prefix":"10.31083","volume":"25","author":[{"given":"Yu-Jie","family":"Zhai","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Shanxi Key Laboratory of Metabolic-Immune Homeostasis and Drug Innovation, Shanxi Medical University, 030600 Jinzhong, Shanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Qi","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Neurology, First Hospital of Shanxi Medical University, 030001 Taiyuan, Shanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Shanxi Key Laboratory of Metabolic-Immune Homeostasis and Drug Innovation, Shanxi Medical University, 030600 Jinzhong, Shanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Hong","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurology, First Hospital of Shanxi Medical University, 030001 Taiyuan, Shanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1021-1800","authenticated-orcid":true,"given":"Yan-Ying","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Shanxi Key Laboratory of Metabolic-Immune Homeostasis and Drug Innovation, Shanxi Medical University, 030600 Jinzhong, Shanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"GBD 2021 Stroke Risk Factor Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990\u20132021: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet Neurology. 2024; 23: 973\u20131003.","DOI":"10.1016\/S1474-4422(24)00369-7"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Feigin VL, Brainin M, Norrving B, Martins SO, Pandian J, Lindsay P, et al. World Stroke Organization: Global Stroke Fact Sheet 2025. International Journal of Stroke: Official Journal of the International Stroke Society. 2025; 20: 132\u2013144.","DOI":"10.1177\/17474930241308142"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Warner JJ, Harrington RA, Sacco RL, Elkind MSV. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke. Stroke. 2019; 50: 3331\u20133332.","DOI":"10.1161\/STROKEAHA.119.027708"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Zhang Y, Lei L, Zhou H, Lu X, Cai F, Li T. Roles of Micro Ribonucleic Acids in Astrocytes After Cerebral Stroke. Frontiers in Cellular Neuroscience. 2022; 16: 890762.","DOI":"10.3389\/fncel.2022.890762"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Ernst AS, B\u00f6hler LI, Hagenston AM, Hoffmann A, Heiland S, Sticht C, et al. EphB2-dependent signaling promotes neuronal excitotoxicity and inflammation in the acute phase of ischemic stroke. Acta Neuropathologica Communications. 2019; 7: 15.","DOI":"10.1186\/s40478-019-0669-7"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Planas AM. Role of microglia in stroke. Glia. 2024; 72: 1016\u20131053.","DOI":"10.1002\/glia.24501"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Choi DH, Choi IA, Lee J. Role of NADPH Oxidases in Stroke Recovery. Antioxidants (Basel, Switzerland). 2024; 13: 1065.","DOI":"10.3390\/antiox13091065"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Li P, Stetler RA, Leak RK, Shi Y, Li Y, Yu W, et al. Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery. Neuropharmacology. 2018; 134: 208\u2013217.","DOI":"10.1016\/j.neuropharm.2017.11.011"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Weber RZ, Rust R, Tackenberg C. How neural stem cell therapy promotes brain repair after stroke. Stem Cell Reports. 2025; 20: 102507.","DOI":"10.1016\/j.stemcr.2025.102507"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiological Reviews. 2008; 88: 887\u2013918.","DOI":"10.1152\/physrev.00033.2007"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. The Journal of Clinical Investigation. 2001; 108: 779\u2013784.","DOI":"10.1172\/JCI13992"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Potere N, Del Buono MG, Niccoli G, Crea F, Toldo S, Abbate A. Developing LRP1 Agonists into a Therapeutic Strategy in Acute Myocardial Infarction. International Journal of Molecular Sciences. 2019; 20: 544.","DOI":"10.3390\/ijms20030544"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Potere N, Del Buono MG, Mauro AG, Abbate A, Toldo S. Low Density Lipoprotein Receptor-Related Protein-1 in Cardiac Inflammation and Infarct Healing. Frontiers in Cardiovascular Medicine. 2019; 6: 51.","DOI":"10.3389\/fcvm.2019.00051"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Liu Q, Zhang J, Zerbinatti C, Zhan Y, Kolber BJ, Herz J, et al. Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system. PLoS Biology. 2011; 9: e1000575.","DOI":"10.1371\/journal.pbio.1000575"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Gan M, Jiang P, McLean P, Kanekiyo T, Bu G. Low-density lipoprotein receptor-related protein 1 (LRP1) regulates the stability and function of GluA1 \u03b1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor in neurons. PLoS One. 2014; 9: e113237.","DOI":"10.1371\/journal.pone.0113237"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Hennen E, Safina D, Haussmann U, W\u00f6rsd\u00f6rfer P, Edenhofer F, Poetsch A, et al. A LewisX glycoprotein screen identifies the low density lipoprotein receptor-related protein 1 (LRP1) as a modulator of oligodendrogenesis in mice. The Journal of Biological Chemistry. 2013; 288: 16538\u201316545.","DOI":"10.1074\/jbc.M112.419812"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Harriott AM, Heckman MG, Rayaprolu S, Soto-Ortolaza AI, Diehl NN, Kanekiyo T, et al. Low density lipoprotein receptor related protein 1 and 6 gene variants and ischaemic stroke risk. European Journal of Neurology. 2015; 22: 1235\u20131241.","DOI":"10.1111\/ene.12735"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Li JM, Yu JY, Sun T, Fan ML, Liu QQ, Li X, et al. Luteolin Improves BBB Integrity Following Ischemic Stroke Injury by Downregulating the Expression of LRP1 and MMP9. Phytotherapy Research. 2026; 40: 4898\u20134912.","DOI":"10.1002\/ptr.70121"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Xie G, Jiang G, Huang L, Sun S, Li X, Wu B, et al. Asparagine Endopeptidase Inhibition Attenuates Tissue Plasminogen Activator-Induced Brain Hemorrhagic Transformation After Ischemic Stroke. CNS Neuroscience & Therapeutics. 2025; 31: e70345.","DOI":"10.1111\/cns.70345"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Li DD, Pang HG, Song JN, Zhao YL, Zhang BF, Ma XD, et al. Receptor-associated protein promotes t-PA expression, reduces PAI-1 expression and improves neurorecovery after acute ischemic stroke. Journal of the Neurological Sciences. 2015; 350: 84\u201389.","DOI":"10.1016\/j.jns.2015.02.022"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Zhang X, Polavarapu R, She H, Mao Z, Yepes M. Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein mediate cerebral ischemia-induced nuclear factor-kappaB pathway activation. The American Journal of Pathology. 2007; 171: 1281\u20131290.","DOI":"10.2353\/ajpath.2007.070472"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Zhou J, Zhang L, Peng J, Zhang X, Zhang F, Wu Y, et al. Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation. Cell Metabolism. 2024; 36: 2054\u20132068.e14.","DOI":"10.1016\/j.cmet.2024.05.016"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Wan T, Zhu W, Zhao Y, Zhang X, Ye R, Zuo M, et al. Astrocytic phagocytosis contributes to demyelination after focal cortical ischemia in mice. Nature Communications. 2022; 13: 1134.","DOI":"10.1038\/s41467-022-28777-9"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Darabi S, Gorgich EAC, Moradi F, Rustamzadeh A. Lipidopathy disrupts peripheral and central amyloid clearance in Alzheimer's disease: Where are our knowledge. IBRO Neuroscience Reports. 2025; 18: 191\u2013199.","DOI":"10.1016\/j.ibneur.2025.01.004"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Willnow TE, Rohlmann A, Horton J, Otani H, Braun JR, Hammer RE, et al. RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors. The EMBO Journal. 1996; 15: 2632\u20132639.","DOI":"10.1002\/j.1460-2075.1996.tb00623.x"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Bu G, Geuze HJ, Strous GJ, Schwartz AL. 39 kDa receptor-associated protein is an ER resident protein and molecular chaperone for LDL receptor-related protein. The EMBO Journal. 1995; 14: 2269\u20132280.","DOI":"10.1002\/j.1460-2075.1995.tb07221.x"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Willnow TE, Moehring JM, Inocencio NM, Moehring TJ, Herz J. The low-density-lipoprotein receptor-related protein (LRP) is processed by furin in vivo and in vitro. The Biochemical Journal. 1996; 313: 71\u201376.","DOI":"10.1042\/bj3130071"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Frey ZD, Price DA, Connors KA, Rush RE, Brown G, Sterling CE, et al. LRP1 facilitates Jamestown Canyon virus infection of neurons. Journal of Virology. 2025; 99: e0184125.","DOI":"10.1128\/jvi.01841-25"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Sagare AP, Deane R, Zlokovic BV. Low-density lipoprotein receptor-related protein 1: a physiological A\u03b2 homeostatic mechanism with multiple therapeutic opportunities. Pharmacology & Therapeutics. 2012; 136: 94\u2013105.","DOI":"10.1016\/j.pharmthera.2012.07.008"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Strickland DK, Ranganathan S. Diverse role of LDL receptor-related protein in the clearance of proteases and in signaling. Journal of Thrombosis and Haemostasis: JTH. 2003; 1: 1663\u20131670.","DOI":"10.1046\/j.1538-7836.2003.00330.x"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Chen J, Su Y, Pi S, Hu B, Mao L. The Dual Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Atherosclerosis. Frontiers in Cardiovascular Medicine. 2021; 8: 682389.","DOI":"10.3389\/fcvm.2021.682389"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Beisiegel U, Weber W, Ihrke G, Herz J, Stanley KK. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature. 1989; 341: 162\u2013164.","DOI":"10.1038\/341162a0"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Safina D, Schlitt F, Romeo R, Pflanzner T, Pietrzik CU, Narayanaswami V, et al. Low-density lipoprotein receptor-related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation. Glia. 2016; 64: 1363\u20131380.","DOI":"10.1002\/glia.23009"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Zhuo M, Holtzman DM, Li Y, Osaka H, DeMaro J, Jacquin M, et al. Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2000; 20: 542\u2013549.","DOI":"10.1523\/JNEUROSCI.20-02-00542.2000"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. The Journal of Clinical Investigation. 2003; 112: 1533\u20131540.","DOI":"10.1172\/JCI19212"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Etique N, Verzeaux L, Dedieu S, Emonard H. LRP-1: a checkpoint for the extracellular matrix proteolysis. BioMed Research International. 2013; 2013: 152163.","DOI":"10.1155\/2013\/152163"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Bacskai BJ, Xia MQ, Strickland DK, Rebeck GW, Hyman BT. The endocytic receptor protein LRP also mediates neuronal calcium signaling via N-methyl-D-aspartate receptors. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97: 11551\u201311556.","DOI":"10.1073\/pnas.200238297"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Zhang C, An J, Haile WB, Echeverry R, Strickland DK, Yepes M. Microglial low-density lipoprotein receptor-related protein 1 mediates the effect of tissue-type plasminogen activator on matrix metalloproteinase-9 activity in the ischemic brain. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2009; 29: 1946\u20131954.","DOI":"10.1038\/jcbfm.2009.174"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Goto JJ, Tanzi RE. The role of the low-density lipoprotein receptor-related protein (LRP1) in Alzheimer's A beta generation: development of a cell-based model system. Journal of Molecular Neuroscience: MN. 2002; 19: 37\u201341.","DOI":"10.1007\/s12031-002-0008-4"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Stiles TL, Dickendesher TL, Gaultier A, Fernandez-Castaneda A, Mantuano E, Giger RJ, et al. LDL receptor-related protein-1 is a sialic-acid-independent receptor for myelin-associated glycoprotein that functions in neurite outgrowth inhibition by MAG and CNS myelin. Journal of Cell Science. 2013; 126: 209\u2013220.","DOI":"10.1242\/jcs.113191"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Li Y, Marzolo MP, van Kerkhof P, Strous GJ, Bu G. The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein. The Journal of Biological Chemistry. 2000; 275: 17187\u201317194.","DOI":"10.1074\/jbc.M000490200"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Loukinova E, Ranganathan S, Kuznetsov S, Gorlatova N, Migliorini MM, Loukinov D, et al. Platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of the low density lipoprotein receptor-related protein (LRP). Evidence for integrated co-receptor function between LRP and the PDGF. The Journal of Biological Chemistry. 2002; 277: 15499\u201315506.","DOI":"10.1074\/jbc.M200427200"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Kang LI, Isse K, Koral K, Bowen WC, Muratoglu S, Strickland DK, et al. Tissue-type plasminogen activator suppresses activated stellate cells through low-density lipoprotein receptor-related protein 1. Laboratory Investigation; a Journal of Technical Methods and Pathology. 2015; 95: 1117\u20131129.","DOI":"10.1038\/labinvest.2015.94"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Li Y, van Kerkhof P, Marzolo MP, Strous GJ, Bu G. Identification of a major cyclic AMP-dependent protein kinase A phosphorylation site within the cytoplasmic tail of the low-density lipoprotein receptor-related protein: implication for receptor-mediated endocytosis. Molecular and Cellular Biology. 2001; 21: 1185\u20131195.","DOI":"10.1128\/MCB.21.4.1185-1195.2001"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Li M, Wang T, Zhong Y, Wang Z, Li W, Wang Z, et al. LMO7 Suppresses Tumor-Associated Macrophage Phagocytosis of Tumor Cells Through Degradation of LRP1. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2025; 13: e11162.","DOI":"10.1002\/advs.202511162"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"Brophy ML, Dong Y, Tao H, Yancey PG, Song K, Zhang K, et al. Myeloid-Specific Deletion of Epsins 1 and 2 Reduces Atherosclerosis by Preventing LRP-1 Downregulation. Circulation Research. 2019; 124: e6\u2013e19.","DOI":"10.1161\/CIRCRESAHA.118.313028"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"Cal R, Garc\u00eda-Arguinzonis M, Revuelta-L\u00f3pez E, Castellano J, Padr\u00f3 T, Badimon L, et al. Aggregated low-density lipoprotein induces LRP1 stabilization through E3 ubiquitin ligase CHFR downregulation in human vascular smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 2013; 33: 369\u2013377.","DOI":"10.1161\/ATVBAHA.112.300748"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Wang S, Mao Y, Narimatsu Y, Ye Z, Tian W, Goth CK, et al. Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions. The Journal of Biological Chemistry. 2018; 293: 7408\u20137422.","DOI":"10.1074\/jbc.M117.817981"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Polavarapu R, Gongora MC, Yi H, Ranganthan S, Lawrence DA, Strickland D, et al. Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit. Blood. 2007; 109: 3270\u20133278.","DOI":"10.1182\/blood-2006-08-043125"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"Polavarapu R, An J, Zhang C, Yepes M. Regulated intramembrane proteolysis of the low-density lipoprotein receptor-related protein mediates ischemic cell death. The American Journal of Pathology. 2008; 172: 1355\u20131362.","DOI":"10.2353\/ajpath.2008.070975"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"Arai AL, Migliorini M, Au DT, Hahn-Dantona E, Peeney D, Stetler-Stevenson WG, et al. High-Affinity Binding of LDL Receptor-Related Protein 1 to Matrix Metalloprotease 1 Requires Protease:Inhibitor Complex Formation. Biochemistry. 2020; 59: 2922\u20132933.","DOI":"10.1021\/acs.biochem.0c00442"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"Ma Z, Thomas KS, Webb DJ, Moravec R, Salicioni AM, Mars WM, et al. Regulation of Rac1 activation by the low density lipoprotein receptor-related protein. The Journal of Cell Biology. 2002; 159: 1061\u20131070.","DOI":"10.1083\/jcb.200207070"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Meng H, Chen G, Zhang X, Wang Z, Thomas DG, Giordano TJ, et al. Stromal LRP1 in lung adenocarcinoma predicts clinical outcome. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research. 2011; 17: 2426\u20132433.","DOI":"10.1158\/1078-0432.CCR-10-2385"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Klecker PH, Fritzen L, Mazura AD, Weggen S, Pietrzik CU. Antibody-mediated inhibition of tissue-type plasminogen activator binding to the low-density lipoprotein receptor-related protein 1 as a potential beneficial modulator for stroke therapy. Journal of Cellular Biochemistry. 2023; 124: 1040\u20131049.","DOI":"10.1002\/jcb.30431"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"Wohlford GF, Buckley LF, Kadariya D, Park T, Chiabrando JG, Carbone S, et al. A phase 1 clinical trial of SP16, a first-in-class anti-inflammatory LRP1 agonist, in healthy volunteers. PloS One. 2021; 16: e0247357.","DOI":"10.1371\/journal.pone.0247357"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"Soler Y, Rodriguez M, Austin D, Gineste C, Gelber C, El-Hage N. SERPIN-Derived Small Peptide (SP16) as a Potential Therapeutic Agent against HIV-Induced Inflammatory Molecules and Viral Replication in Cells of the Central Nervous System. Cells. 2023; 12: 632.","DOI":"10.3390\/cells12040632"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"Yang CJ, Li X, Feng XQ, Chen Y, Feng JG, Jia J, et al. Activation of LRP1 Ameliorates Cerebral Ischemia\/Reperfusion Injury and Cognitive Decline by Suppressing Neuroinflammation and Oxidative Stress through TXNIP\/NLRP3 Signaling Pathway in Mice. Oxidative Medicine and Cellular Longevity. 2022; 2022: 8729398.","DOI":"10.1155\/2022\/8729398"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"Incontro S, Musella ML, Sammari M, Di Scala C, Fantini J, Debanne D. Lipids shape brain function through ion channel and receptor modulations: physiological mechanisms and clinical perspectives. Physiological Reviews. 2025; 105: 137\u2013207.","DOI":"10.1152\/physrev.00004.2024"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"Liu Q, Trotter J, Zhang J, Peters MM, Cheng H, Bao J, et al. Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2010; 30: 17068\u201317078.","DOI":"10.1523\/JNEUROSCI.4067-10.2010"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Kadry H, Noorani B, Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids and Barriers of the CNS. 2020; 17: 69.","DOI":"10.1186\/s12987-020-00230-3"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"Wang Y, Zhu Y, Wang J, Dong L, Liu S, Li S, et al. Purinergic signaling: A gatekeeper of blood-brain barrier permeation. Frontiers in Pharmacology. 2023; 14: 1112758.","DOI":"10.3389\/fphar.2023.1112758"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"Feng D, Wang L, Hu A, Zhang S. Mechanisms of Astrocyte Action in the Blood Brain Barrier: From Structural Support to Dynamic Regulation. Journal of Integrative Neuroscience. 2025; 24: 45223.","DOI":"10.31083\/JIN45223"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"Nikolakopoulou AM, Wang Y, Ma Q, Sagare AP, Montagne A, Huuskonen MT, et al. Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A. The Journal of Experimental Medicine. 2021; 218: e20202207.","DOI":"10.1084\/jem.20202207"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"Storck SE, Kurtyka M, Pietrzik CU. Brain endothelial LRP1 maintains blood-brain barrier integrity. Fluids and Barriers of the CNS. 2021; 18: 27.","DOI":"10.1186\/s12987-021-00260-5"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"Miller DS. Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends in Pharmacological Sciences. 2010; 31: 246\u2013254.","DOI":"10.1016\/j.tips.2010.03.003"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"Li J, Han W, Wu K, Li YD, Liu Q, Lu W. A Conserved Tyrosine Residue in Slitrk3 Carboxyl-Terminus Is Critical for GABAergic Synapse Development. Frontiers in Molecular Neuroscience. 2019; 12: 213.","DOI":"10.3389\/fnmol.2019.00213"},{"key":"ref67","doi-asserted-by":"publisher","unstructured":"May P, Rohlmann A, Bock HH, Zurhove K, Marth JD, Schomburg ED, et al. Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice. Molecular and Cellular Biology. 2004; 24: 8872\u20138883.","DOI":"10.1128\/MCB.24.20.8872-8883.2004"},{"key":"ref68","doi-asserted-by":"publisher","unstructured":"Nakajima C, Kulik A, Frotscher M, Herz J, Sch\u00e4fer M, Bock HH, et al. Low density lipoprotein receptor-related protein 1 (LRP1) modulates N-methyl-D-aspartate (NMDA) receptor-dependent intracellular signaling and NMDA-induced regulation of postsynaptic protein complexes. The Journal of Biological Chemistry. 2013; 288: 21909\u201321923.","DOI":"10.1074\/jbc.M112.444364"},{"key":"ref69","doi-asserted-by":"publisher","unstructured":"Maier W, Bednorz M, Meister S, Roebroek A, Weggen S, Schmitt U, et al. LRP1 is critical for the surface distribution and internalization of the NR2B NMDA receptor subtype. Molecular Neurodegeneration. 2013; 8: 25.","DOI":"10.1186\/1750-1326-8-25"},{"key":"ref70","doi-asserted-by":"publisher","unstructured":"Romeo R, Glotzbach K, Scheller A, Faissner A. Deletion of LRP1 From Astrocytes Modifies Neuronal Network Activity in an in vitro Model of the Tripartite Synapse. Frontiers in Cellular Neuroscience. 2020; 14: 567253.","DOI":"10.3389\/fncel.2020.567253"},{"key":"ref71","doi-asserted-by":"publisher","unstructured":"Shi W, Bi S, Dai Y, Yang K, Zhao Y, Zhang Z. Clobetasol propionate enhances neural stem cell and oligodendrocyte differentiation. Experimental and Therapeutic Medicine. 2019; 18: 1258\u20131266.","DOI":"10.3892\/etm.2019.7692"},{"key":"ref72","doi-asserted-by":"publisher","unstructured":"Wang M, Ahmad SN, Reed P, Sprague S, Sayre NL. Knockout of Low-Density Lipoprotein Receptor-Related Protein 1 From Astrocytes in Adult Mice Accelerates Long-Term Functional Recovery After Ischemic Stroke. Brain and Behavior. 2026; 16: e71300.","DOI":"10.1002\/brb3.71300"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"Lok KZ, Manzanero S, Arumugam TV. Neuronal low-density lipoprotein receptor-related protein 1 (LRP1) enhances the anti-apoptotic effect of intravenous immunoglobulin (IVIg) in ischemic stroke. Brain Research. 2016; 1644: 192\u2013202.","DOI":"10.1016\/j.brainres.2016.05.023"},{"key":"ref74","doi-asserted-by":"publisher","unstructured":"Ye J, Bi X, Deng S, Wang X, Liu Z, Suo Q, et al. Hypoxanthine is a metabolic biomarker for inducing GSDME-dependent pyroptosis of endothelial cells during ischemic stroke. Theranostics. 2024; 14: 6071\u20136087.","DOI":"10.7150\/thno.100090"},{"key":"ref75","doi-asserted-by":"publisher","unstructured":"Chang L, Hu L, Wei C, Zhang H, Liu S. Chinese medicine Tongxinluo capsule protects against blood-brain barrier disruption after ischemic stroke by inhibiting the low-density lipoprotein receptor-related protein 1 pathway in mice. Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association. 2020; 29: 105071.","DOI":"10.1016\/j.jstrokecerebrovasdis.2020.105071"},{"key":"ref76","doi-asserted-by":"publisher","unstructured":"Lu D, Mai HC, Liang YB, Xu BD, Xu AD, Zhang YS. Beneficial Role of Rosuvastatin in Blood-Brain Barrier Damage Following Experimental Ischemic Stroke. Frontiers in Pharmacology. 2018; 9: 926.","DOI":"10.3389\/fphar.2018.00926"},{"key":"ref77","doi-asserted-by":"publisher","unstructured":"An J, Zhang C, Polavarapu R, Zhang X, Zhang X, Yepes M. Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein induce Akt phosphorylation in the ischemic brain. Blood. 2008; 112: 2787\u20132794.","DOI":"10.1182\/blood-2008-02-141630"},{"key":"ref78","doi-asserted-by":"publisher","unstructured":"Wang R, Zhu Y, Liu Z, Chang L, Bai X, Kang L, et al. Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke. Blood. 2021; 138: 91\u2013103.","DOI":"10.1182\/blood.2020008913"},{"key":"ref79","doi-asserted-by":"publisher","unstructured":"Li RHL, Ng G, Tablin F. Lipopolysaccharide-induced neutrophil extracellular trap formation in canine neutrophils is dependent on histone H3 citrullination by peptidylarginine deiminase. Veterinary Immunology and Immunopathology. 2017; 193\u2013194: 29\u201337.","DOI":"10.1016\/j.vetimm.2017.10.002"},{"key":"ref80","doi-asserted-by":"publisher","unstructured":"Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, Gallant M, et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proceedings of the National Academy of Sciences of the United States of America. 2013; 110: 8674\u20138679.","DOI":"10.1073\/pnas.1301059110"},{"key":"ref81","doi-asserted-by":"publisher","unstructured":"Lei W, Dong Y, Zhuang H, Wu Q, Zhang X, Wu X, et al. Astrocytic SIRT3 Alleviates Neuroinflammatory Responses After Cerebral Ischemia\/reperfusion by Inhibiting the cGAS-STING Pathway. Inflammation. 2026; 49: 32.","DOI":"10.1007\/s10753-025-02388-0"},{"key":"ref82","doi-asserted-by":"publisher","unstructured":"Zhang C, An J, Strickland DK, Yepes M. The low-density lipoprotein receptor-related protein 1 mediates tissue-type plasminogen activator-induced microglial activation in the ischemic brain. The American Journal of Pathology. 2009; 174: 586\u2013594.","DOI":"10.2353\/ajpath.2009.080661"},{"key":"ref83","doi-asserted-by":"publisher","unstructured":"Sil S, Thangaraj A, Oladapo A, Hu G, Kutchy NA, Liao K, et al. Role of Autophagy in HIV-1 and Drug Abuse-Mediated Neuroinflammaging. Viruses. 2022; 15: 44.","DOI":"10.3390\/v15010044"},{"key":"ref84","doi-asserted-by":"publisher","unstructured":"Ni XC, Wang HF, Cai YY, Yang D, Alolga RN, Liu B, et al. Ginsenoside Rb1 inhibits astrocyte activation and promotes transfer of astrocytic mitochondria to neurons against ischemic stroke. Redox Biology. 2022; 54: 102363.","DOI":"10.1016\/j.redox.2022.102363"},{"key":"ref85","doi-asserted-by":"publisher","unstructured":"Yuan Y, Tian Y, Jiang H, Cai LY, Song J, Peng R, et al. Mechanism of PGC-1\u03b1-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury. Frontiers in Molecular Neuroscience. 2023; 16: 1224964.","DOI":"10.3389\/fnmol.2023.1224964"},{"key":"ref86","doi-asserted-by":"publisher","unstructured":"Berlet R, Anthony S, Brooks B, Wang ZJ, Sadanandan N, Shear A, et al. Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke. Biomolecules. 2021; 11: 1316.","DOI":"10.3390\/biom11091316"},{"key":"ref87","doi-asserted-by":"publisher","unstructured":"Yamazaki R, Ohno N. The potential of repurposing clemastine to promote remyelination. Frontiers in Cellular Neuroscience. 2025; 19: 1582902.","DOI":"10.3389\/fncel.2025.1582902"},{"key":"ref88","doi-asserted-by":"publisher","unstructured":"Song S, Yu L, Hasan MN, Paruchuri SS, Mullett SJ, Sullivan MLG, et al. Elevated microglial oxidative phosphorylation and phagocytosis stimulate post-stroke brain remodeling and cognitive function recovery in mice. Communications Biology. 2022; 5: 35.","DOI":"10.1038\/s42003-021-02984-4"},{"key":"ref89","doi-asserted-by":"publisher","unstructured":"Wang S, Li C, Kang X, Su X, Liu Y, Wang Y, et al. Agomelatine promotes differentiation of oligodendrocyte precursor cells and preserves white matter integrity after cerebral ischemic stroke. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2024; 44: 1487\u20131500.","DOI":"10.1177\/0271678X241260100"},{"key":"ref90","doi-asserted-by":"publisher","unstructured":"Zhang Q, Zhu W, Xu F, Dai X, Shi L, Cai W, et al. The interleukin-4\/PPAR\u03b3 signaling axis promotes oligodendrocyte differentiation and remyelination after brain injury. PLoS Biology. 2019; 17: e3000330.","DOI":"10.1371\/journal.pbio.3000330"},{"key":"ref91","doi-asserted-by":"publisher","unstructured":"Ruan H, Chai Z, Shen Q, Chen X, Su B, Xie C, et al. A novel peptide ligand RAP12 of LRP1 for glioma targeted drug delivery. Journal of Controlled Release: Official Journal of the Controlled Release Society. 2018; 279: 306\u2013315.","DOI":"10.1016\/j.jconrel.2018.04.035"},{"key":"ref92","doi-asserted-by":"publisher","unstructured":"Yang P, Li Y, Qian K, Zhou L, Cheng Y, Wu J, et al. Precise Modulation of Pericyte Dysfunction by a Multifunctional Nanoprodrug to Ameliorate Alzheimer's Disease. ACS Nano. 2024; 18: 14348\u201314366.","DOI":"10.1021\/acsnano.4c00480"},{"key":"ref93","doi-asserted-by":"publisher","unstructured":"Kim ES, Kim D, Nyberg S, Poma A, Cecchin D, Jain SA, et al. LRP-1 functionalized polymersomes enhance the efficacy of carnosine in experimental stroke. Scientific Reports. 2020; 10: 699.","DOI":"10.1038\/s41598-020-57685-5"}],"container-title":["Journal of Integrative Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/25\/9\/10.31083\/JIN53774","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:17:14Z","timestamp":1790698634000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/25\/9\/10.31083\/JIN53774"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":93,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026]]}},"alternative-id":["S0219-6352(26)01172-1"],"URL":"https:\/\/doi.org\/10.31083\/jin53774","relation":{},"ISSN":["0219-6352","1757-448X"],"issn-type":[{"value":"0219-6352","type":"print"},{"value":"1757-448X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]},"article-number":"53774"}}