Krüppel-like factor 4 transcription factor in blood–brain barrier endothelial cells: A potential role in Alzheimer's disease

Abstract

Alzheimer's disease is the most prevalent chronic neurodegenerative disorder worldwide, with no sufficient cure. Ongoing research is focused on developing new therapies aimed at preventing or delaying the onset of symptoms, slowing disease progression, and improving cognitive and behavioral outcomes in individuals affected by Alzheimer's disease. Among the various pathological changes associated with this condition, blood–brain barrier (BBB) leakage plays a crucial role as it serves as a vital boundary for maintaining central nervous system (CNS) health. Preserving the integrity and functionality of the BBB is essential to protect the brain from amyloid-β accumulation, neuroinflammation, and neuronal degeneration. This review summarizes models of Alzheimer's disease characterized by BBB leakage over time. More importantly, we introduce Krüppel-like factor 4 (KLF4), a transcription factor involved in vascular systems, and discuss its relevance to Alzheimer's disease. By elucidating the functions of KLF4 within both vascular and CNSs, this review highlights its potential role in modulating BBB integrity in Alzheimer's pathology, which may contribute to therapeutic strategies for managing this debilitating condition.

Keywords

Alzheimer's disease / blood–brain barrier / endothelial cells / Krüppel-like factor 4

References

[1] Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease. Lancet. 2021; 397(10284): 1577-1590.

[2] Cheng X, Yang Y, Schwebel DC, et al. Population ageing and mortality during 1990-2017: a global decomposition analysis. PLoS Med. 2020; 17(6): e1003138.

[3] Li X, Feng X, Sun X, Hou N, Han F, Liu Y. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2019. Front Aging Neurosci. 2022; 14: 937486.

[4] Nandi A, Counts N, Chen S, et al. Global and regional projections of the economic burden of Alzheimer's disease and related dementias from 2019 to 2050: a value of statistical life approach. EClinicalMedicine. 2022; 51: 101580.

[5] Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018; 14(3): 133-150.

[6] Kurz C, Walker L, Rauchmann BS, Perneczky R. Dysfunction of the blood-brain barrier in Alzheimer's disease: evidence from human studies. Neuropathol Appl Neurobiol. 2022; 48(3): e12782.

[7] Lacoste B, Prat A, Freitas-Andrade M, Gu C. The blood-brain barrier: composition, properties, and roles in brain health. Cold Spring Harb Perspect Biol. 2024;a041422.

[8] Galea I. The blood-brain barrier in systemic infection and inflammation. Cell Mol Immunol. 2021; 18(11): 2489-2501.

[9] Sethi P, Bhaskar R, Singh KK, et al. Exploring advancements in early detection of Alzheimer's disease with molecular assays and animal models. Ageing Res Rev. 2024; 100: 102411.

[10] Chavan RS, Supalkar KV, Sadar SS, Vyawahare NS. Animal models of Alzheimer's disease: an originof innovativetreatments and insight to the disease's etiology. Brain Res. 2023; 1814: 148449.

[11] Nakai T, Yamada K, Mizoguchi H. Alzheimer's disease animal models: elucidation of biomarkers and therapeutic Approaches for cognitive impairment. Int J Mol Sci. 2021; 22(11): 5549.

[12] Rapaka D, Adiukwu PC, Bitra VR. Experimentally induced animal models for cognitive dysfunction and Alzheimer's disease. MethodsX. 2022; 9: 101933.

[13] Youssef SA, Capucchio MT, Rofina JE, et al. Pathology of the aging brain in domestic and laboratory animals, and animal models of human neurodegenerative diseases. Vet Pathol. 2016; 53(2): 327-348.

[14] Chen ZY, Zhang Y. Animal models of Alzheimer's disease: applications, evaluation, and perspectives. Zool Res. 2022; 43(6): 1026-1040.

[15] Huang X, Qi J, Su Y, et al. Endothelial DR6 in blood-brain barrier malfunction in Alzheimer's disease. Cell Death Dis. 2024; 15(4): 258.

[16] Grammas P. Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer's disease. J Neuroinflammation. 2011; 8: 26.

[17] Ritson M, Wheeler-Jones CPD, Stolp HB. Endothelial dysfunction in neurodegenerative disease: is endothelial inflammation an overlooked druggable target? J Neuroimmunol. 2024; 391: 578363.

[18] Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci. 2016; 19(6): 771-783.

[19] Bell RD, Winkler EA, Sagare AP, et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010; 68(3): 409-427.

[20] Barisano G, Montagne A, Kisler K, Schneider JA, Wardlaw JM, Zlokovic BV. Blood-brain barrier link to human cognitive impairment and Alzheimer's disease. Nat Cardiovasc Res. 2022; 1(2): 108-115.

[21] Keep RF, Andjelkovic AV, Xiang J, et al. Brain endothelial cell junctions after cerebral hemorrhage: changes, mechanisms and therapeutic targets. J Cereb Blood Flow Metab. 2018; 38(8): 1255-1275.

[22] Jiang S, Xia R, Jiang Y, Wang L, Gao F. Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier. PLoS One. 2014; 9(2): e86407.

[23] Reichenbach N, Delekate A, Plescher M, et al. Inhibition of Stat3-mediated astrogliosis ameliorates pathology in an Alzheimer's disease model. EMBO Mol Med. 2019; 11(2): e9665.

[24] Montagne A, Zhao Z, Zlokovic BV. Alzheimer's disease: a matter of blood-brain barrier dysfunction? J Exp Med. 2017; 214(11): 3151-3169.

[25] Nehra G, Bauer B, Hartz AMS. Blood-brain barrier leakage in Alzheimer's disease: from discovery to clinical relevance. Pharmacol Ther. 2022; 234: 108119.

[26] Bell RD, Winkler EA, Singh I, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin a. Nature. 2012; 485(7399): 512-516.

[27] Barisano G, Kisler K, Wilkinson B, et al. A “multi-omics” analysis of blood-brain barrier and synaptic dysfunction in APOE4 mice. J Exp Med. 2022; 219(11): e20221137.

[28] Wang Y, Zhang R, Tao C, et al. Blood-brain barrier disruption and perivascular Beta-amyloid accumulation in the brain of aged rats with spontaneous hypertension: evaluation with dynamic contrast-enhanced magnetic resonance imaging. Korean J Radiol. 2018; 19(3): 498-507.

[29] Ma Y, Sun W, Bai J, et al. Targeting blood brain barrier-remote ischemic conditioning alleviates cognitive impairment in female APP/PS1 rats. CNS Neurosci Ther. 2024; 30(2): e14613.

[30] Joshi P, Liang JO, DiMonte K, Sullivan J, Pimplikar SW. Amyloid precursor protein is required for convergent-extension movements during zebrafish development. Dev Biol. 2009; 335(1): 1-11.

[31] Geling A, Steiner H, Willem M, Bally-Cuif L, Haass C. A gamma-secretase inhibitor blocks notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep. 2002; 3(7): 688-694.

[32] Bai Q, Burton EA. Zebrafish models of tauopathy. Biochim Biophys Acta. 2011; 1812(3): 353-363.

[33] de Sousa AA, Rigby Dames BA, Graff EC, Mohamedelhassan R, Vassilopoulos T, Charvet CJ. Going beyond established model systems of Alzheimer's disease: companion animals provide novel insights into the neurobiology of aging. Commun Biol. 2023; 6(1): 655.

[34] Elfenbein HA, Rosen RF, Stephens SL, et al. Cerebral beta-amyloid angiopathy in aged squirrel monkeys. Histol Histopathol. 2007; 22(2): 155-167.

[35] Nystuen KL, McNamee SM, Akula M, Holton KM, DeAngelis MM, Haider NB. Alzheimer's disease: models and molecular mechanisms informing disease and treatments. Bioengineering (Basel). 2024; 11(1): 45.

[36] Yue F, Feng S, Lu C, et al. Synthetic amyloid-β oligomers drive early pathological progression of Alzheimer's disease in nonhuman primates. iScience. 2021; 24(10): 103207.

[37] Jiang Z, Wang J, Qin Y, et al. A nonhuman primate model with Alzheimer's disease-like pathology induced by hippocampal overexpression of human tau. Alzheimers Res Ther. 2024; 16(1): 22.

[38] Head E. A canine model of human aging and Alzheimer's disease. Biochim Biophys Acta. 2013; 1832(9): 1384-1389.

[39] Su MY, Head E, Brooks WM, et al. Magnetic resonance imaging of anatomic and vascular characteristics in a canine model of human aging. Neurobiol Aging. 1998; 19(5): 479-485.

[40] Yang JH, Petty CA, Dixon-McDougall T, et al. Chemically induced reprogramming to reverse cellular aging. Aging. 2023; 15(13): 5966-5989.

[41] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4): 663-676.

[42] Zhang X, Wang L, Han Z, et al. KLF4 alleviates cerebral vascular injury by ameliorating vascular endothelial inflammation and regulating tight junction protein expression following ischemic stroke. J Neuroinflammation. 2020; 17(1): 107.

[43] Segre JA, Bauer C, Fuchs E. Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet. 1999 Aug; 22(4): 356-360.

[44] Yoshida T, Gan Q, Franke AS, et al. Smooth and cardiac muscle-selective knock-out of Kruppel-like factor 4 causes postnatal death and growth retardation. J Biol Chem. 2010; 285(27): 21175-21184.

[45] Haskins RM, Nguyen AT, Alencar GF, et al. Klf4 has an unexpected protective role in perivascular cells within the microvasculature. Am J Physiol Heart Circ Physiol. 2018; 315(2): H402-H414.

[46] Yoshida T, Yamashita M, Horimai C, Hayashi M. Deletion of Kruppel-like factor 4 in endothelial and hematopoietic cells enhances neointimal formation following vascular injury. J Am Heart Assoc. 2014; 3(1): e000622.

[47] Sangwung P, Zhou G, Nayak L, et al. KLF2 and KLF4 control endothelial identity and vascular integrity. JCI Insight. 2017; 2(4): e91700.

[48] Cowan CE, Kohler EE, Dugan TA, Mirza MK, Malik AB, Wary KK. Kruppel-like factor-4 transcriptionally regulates VE-cadherin expression and endothelial barrier function. Circ Res. 2010; 107(8): 959-966.

[49] Ma J, Wang P, Liu Y, Zhao L, Li Z, Xue Y. Kruppel-like factor 4 regulates blood-tumor barrier permeability via ZO-1, occludin and claudin-5. J Cell Physiol. 2014; 229(7): 916-926.

[50] Yu M, Feng HJ, Abdalla AME, Teng YF, Li Q. Apelin-13 promotes late endothelial progenitor cells differentiation by regulating Kruppel-like factor 4. Eur Rev Med Pharmacol Sci. 2019; 23(16): 7098-7109.

[51] Boriushkin E, Zhang H, Becker M, et al. Kruppel-like factor 4 regulates developmental angiogenesis through disruption of the RBP-J-NICD-MAML complex in intron 3 of Dll4. Angiogenesis. 2019; 22(2): 295-309.

[52] Wang Y, Yang C, Gu Q, et al. KLF4 promotes angiogenesis by activating VEGF signaling in human retinal microvascular endothelial cells. PLoS One. 2015; 10(6): e0130341.

[53] Denis JF, Diagbouga MR, Molica F, et al. KLF4-induced Connexin40 expression contributes to arterial endothelial quiescence. Front Physiol. 2019; 10: 80.

[54] Hale AT, Tian H, Anih E, et al. Endothelial Kruppel-like factor 4 regulates angiogenesis and the notch signaling pathway. J Biol Chem. 2014; 289(17): 12016-12028.

[55] Zhang Y, Zhang X-H, Zheng B, et al. Tongxinluo protects against hypoxia-induced breakdown of the endothelial barrier through inducing tight junction protein expression. Int J Clin Exp Med. 2016; 9(8): 15699-15708.

[56] Zhang X, Chen J, Sun L, Xu Y. SIRT1 deacetylates KLF4 to activate Claudin-5 transcription in ovarian cancer cells. J Cell Biochem. 2018; 119(2): 2418-2426.

[57] Sze KL, Lee WM, Lui WY. Expression of CLMP, a novel tight junction protein, is mediated via the interaction of GATA with the Kruppel family proteins, KLF4 and Sp1, in mouse TM4 Sertoli cells. J Cell Physiol. 2008; 214(2): 334-344.

[58] Delp EE, Swamynathan S, Kao WW, Swamynathan SK. Spatiotemporally regulated ablation of Klf4 in adult mouse corneal epithelial cells results in altered epithelial cell identity and disrupted homeostasis. Invest Ophthalmol Vis Sci. 2015; 56(6): 3549-3558.

[59] Cho DI, Ahn MJ, Cho HH, et al. ANGPTL4 stabilizes atherosclerotic plaques and modulates the phenotypic transition of vascular smooth muscle cells through KLF4 downregulation. Exp Mol Med. 2023; 55(2): 426-442.

[60] Huang Y, Han X, Tang J, Long X, Wang X. Salidroside inhibits endothelial-mesenchymal transition via the KLF4/eNOS signaling pathway. Mol Med Rep. 2021; 24(4): 692.

[61] Hamik A, Lin Z, Kumar A, et al. Kruppel-like factor 4 regulates endothelial inflammation. J Biol Chem. 2007; 282(18): 13769-13779.

[62] Yuan J, Que R, Zhao W, Song F, Cao Y, Yu B. Influences of lysine-specific demethylase 1 inhibitors on NO synthase-Kruppel-like factor pathways in human endothelial cells in vitro and zebrafish (Danio rerio) larvae in vivo. J Appl Toxicol. 2023; 43(11): 1748-1760.

[63] Zhu X, Du J, Yu J, et al. LncRNA NKILA regulates endothelium inflammation by controlling a NF-κB/KLF4 positive feedback loop. J Mol Cell Cardiol. 2019; 126: 60-69.

[64] Zhu X, Du J, Yu J, et al. LncRNA NKILA regulates endothelium inflammation by controlling a NF-kappaB/KLF4 positive feedback loop. J Mol Cell Cardiol. 2019; 126: 60-69.

[65] Cheng Z, Zou X, Jin Y, et al. The role of KLF(4) in Alzheimer's disease. Front Cell Neurosci. 2018; 12: 325.

[66] Heneka MT, Carson MJ, El KJ, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015; 14(4): 388-405.

[67] Li L, Zi X, Hou D, Tu Q. Kruppel-like factor 4 regulates amyloid-beta (Abeta)-induced neuroinflammation in Alzheimer's disease. Neurosci Lett. 2017; 643: 131-137.

[68] Kaushik DK, Gupta M, Das S, Basu A. Kruppel-like factor 4, a novel transcription factor regulates microglial activation and subsequent neuroinflammation. J Neuroinflammation. 2010; 7: 68.

[69] Kaushik DK, Thounaojam MC, Kumawat KL, Gupta M, Basu A. Interleukin-1β orchestrates underlying inflammatory responses in microglia via Krüppel-like factor 4. J NeurochemJ Neurochem. 2013; 127(2): 233-244.

[70] Kaushik DK, Thounaojam MC, Kumawat KL, Gupta M, Basu A. Interleukin-1beta orchestrates underlying inflammatory responses in microglia via Kruppel-like factor 4. J Neurochem. 2013; 127(2): 233-244.

[71] Zhao K, Liu J, Sun T, et al. The miR-25802/KLF4/NF-kappaB signaling axis regulates microglia-mediated neuroinflammation in Alzheimer's disease. Brain Behav Immun. 2024; 118: 31-48.

[72] Zhou B, Zuo YX, Jiang RT. Astrocyte morphology: diversity, plasticity, and role in neurological diseases. CNS Neurosci Ther. 2019; 25(6): 665-673.

[73] Wang C, Li L. The critical role of KLF4 in regulating the activation of A1/A2 reactive astrocytes following ischemic stroke. J Neuroinflammation. 2023; 20(1): 44.

[74] Park JH, Riew TR, Shin YJ, Park JM, Cho JM, Lee MY. Induction of Krüppel-like factor 4 expression in reactive astrocytes following ischemic injury in vitro and in vivo. Histochem Cell Biol. 2014; 141(1): 33-42.

[75] Zhang J, Cui F, Li L, et al. Contrasting effects of Krüppel-like factor 4 on X-ray-induced double-strand and single-strand DNA breaks in mouse astrocytes. Cell Biochem Funct. 2014; 32(3): 241-248.

[76] Nguyen T, Sun F, Su C, Singh M. Pgrmc1/KLF4 signaling mediates the neuron-glia crosstalk as a neuroprotective mechanism. FASEB J. 2015; 29: LB498.

[77] Kumari S, Dhapola R, Reddy DH. Apoptosis in Alzheimer's disease: insight into the signaling pathways and therapeutic avenues. Apoptosis. 2023; 28(7-8): 943-957.

[78] Cui DM, Zeng T, Ren J, et al. KLF4 knockdown attenuates TBI-induced neuronal damage through p53 and JAK-STAT3 signaling. CNS Neurosci Ther. 2017; 23(2): 106-118.

[79] Wang Z, Li J, Wang A, et al. Sevoflurane inhibits traumatic brain injury-induced neuron apoptosis via EZH2-downregulated KLF4/p38 Axis. Front Cell Dev Biol. 2021; 9: 658720.

[80] Huang Z, Liu J, Xu J, Dai L, Wang H. Downregulation of miR-26b attenuates early brain injury induced by subarachnoid hemorrhage via mediating the KLF4/STAT3/HMGB1 axis. Exp Neurol. 2023; 359: 114270.

[81] Hollville E, Romero SE, Deshmukh M. Apoptotic cell death regulation in neurons. FEBS J. 2019; 286(17): 3276-3298.

[82] Cheng Y, Song H, Ming GL, Weng YL. Epigenetic and epitranscriptomic regulation of axon regeneration. Mol Psychiatry. 2023; 28(4): 1440-1450.

[83] Lu Y, Brommer B, Tian X, et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020; 588(7836): 124-129.

[84] Rocha-Martins M, de Toledo BC, Santos-França PL, et al. De novo genesis of retinal ganglion cells by targeted expression of Klf4 in vivo. Development. 2019; 146(16): dev176586.

[85] Cong M, Li J, Wang L, et al. MircoRNA-25-3p in skin precursor cell-induced Schwann cell-derived extracellular vesicles promotes axon regeneration by targeting Tgif1. Exp Neurol. 2024; 376: 114750.

[86] van Battum EY, Verhagen MG, Vangoor VR, et al. An image-based miRNA screen identifies miRNA-135s As regulators of CNS axon growth and regeneration by targeting Krüppel-like factor 4. J Neurosci. 2018; 38(3): 613-630.

[87] Qin S, Zhang CL. Role of Kruppel-like factor 4 in neurogenesis and radial neuronal migration in the developing cerebral cortex. Mol Cell Biol. 2012; 32(21): 4297-4305.

[88] Bychkov ML, Isaev AB, Andreev-Andrievskiy AA, et al. Aβ1-42 accumulation accompanies changed expression of Ly6/uPAR proteins, dysregulation of the cholinergic system, and degeneration of astrocytes in the cerebellum of mouse model of early Alzheimer disease. Int J Mol Sci. 2023; 24(19): 14852.

[89] Wang Q-S, Xiao R-J, Peng J, Yu Z-T, Fu J-Q, Xia Y. Bone marrow mesenchymal stem cell-derived Exosomal KLF4 alleviated ischemic stroke through inhibiting N6-Methyladenosine modification level of Drp1 by targeting lncRNA-ZFAS1. Mol Neurobiol. 2023; 60(7): 3945-3962.

[90] Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer's disease drug development pipeline: 2024. Alzheimers Dement. 2024; 10(2): e12465.

RIGHTS & PERMISSIONS

2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.