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Integrins as receptor targets for neurological disorders
Open accessAbstract
This review focuses on the neurobiology of integrins, pathophysiological roles of integrins in neuroplasticity and nervous system disorders, and therapeutic implications of integrins as potential drug targets and possible delivery pathways. Neuroplasticity is a central phenomenon in many neurological conditions such as seizures, trauma, and traumatic brain injury. During the course of many brain diseases, in addition to intracellular compartment changes, alterations in non-cell compartments such as extracellular matrix (ECM) are recognized as an essential process in forming and reorganizing neural connections. Integrins are heterodimeric transmembrane receptors that mediate cell-ECM and cell-cell adhesion events. Although the mechanisms of neuroplasticity remain unclear, it has been suggested that integrins undergo plasticity including clustering through interactions with ECM proteins, modulating ion channels, intracellular Ca(2+) and protein kinase signaling, and reorganization of cytoskeletal filaments. As cell surface receptors, integrins are central to the pathophysiology of many brain diseases, such as epilepsy, and are potential targets for the development of new drugs for neurological disorders.
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“Among the top enriched up-regulated pathways in the aggressive Lidia group, the integrin and Alzheimer disease-presenilin signaling pathways are well-known gene routes in the development of abnormal aggressive behaviors [48] (Table 3).”
From Gene expression profiles underlying aggressive behavior in the prefrontal cortex of cattle (2021) · cites this paper as [48]
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“Increased expression of integrins contributes to imbalanced synaptic function in specific pathological conditions, such as Alzheimer disease and schizophrenia, both often accompanied by episodic aggression and violence [48].”
From Gene expression profiles underlying aggressive behavior in the prefrontal cortex of cattle (2021) · cites this paper as [48]
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“Interestingly, mossy fibers show immunoreactivity for α2-, β4- and β5-integrins (Wu and Reddy, 2012) while perisynaptic astrocyte processes in stratum lucidum contain β1integrin (Schuster et al.”
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“…subunits α3, α5, α8, α(V), β1, and β3 function in a variety of roles in the brain, including neuronal migration, synapse and dendrite development, morphogenesis and stability, and synaptic plasticity (Gupton and Gertler, 2010; McCarty et al., 2005; Rehberg et al., 2014; Wu and Reddy, 2012).”
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InfluentialMultiscale Mechanobiology in Brain Physiology and Diseases
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“Several treatment approaches include integrin as a direct clinical therapeutic target, modulation of integrin activity, and controlling integrin expression (Wojcik-Stanaszek et al., 2011; Wu & Reddy, 2012).”
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“Cell-matrix adhesion is a vital regulator of many cellular processes (Berrier and Yamada, 2007; Caswell et al., 2009; Danen and Yamada, 2001) and disease conditions (Desgrosellier and Cheresh, 2010; Wu and Reddy, 2012).”
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“The important role of integrins in the regulation of extracellular matrix and synaptic activity is well-established (Wu and Reddy, 2012; Park and Goda, 2016; Lilja and Ivaska, 2018).”
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“Integrins, which mediate ECM signaling events, have been largely involved in brain plasticity and pathophysiology, including oligodendrocyte differentiation and migration [35].”
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Loohuis, N. F. M. O., Kasri, N. N., Glennon, J. C., van Bokhoven, H., Hébert, S. S., Kaplan, B. B., Martens, G. J. M., & Aschrafi, A. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.02.009 · Cited by 30
“Previous research already suggested that defects in the ECMreceptor interaction and actin cytoskeleton pathways may underlie disturbances in proper memory formation (Wu and Reddy, 2012), and may be causative for ID and SZ (Dityatev et al., 2010; Evans et al., 2007).”
BackgroundInfluentialAdhering towards tumorigenicity: altered adhesion mechanisms in glioblastoma cancer stem cells
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LFA-1 Controls Th1 and Th17 Motility Behavior in the Inflamed Central Nervous System
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“between the ECM, the intracellular cytoskeleton, and signaling pathways (63).”
BackgroundHan, C., Zhao, X., Liu, Y., Wang, K., Chen, N., Hu, W., Zhang, J., Ge, M., & Meng, F. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.10.021 · Cited by 27
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“Dystroglycan signaling can also regulate cell migration through its interaction with focal adhesion kinase (FAK) and paxillin [93].”
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“Seizures activate integrin signaling and induce a turnover in adhesive contacts [26, 27], which hypothetically may be linked to increased Ttyh1 expression observed during epileptogenesis and epilepsy [10, 28].”
BackgroundWhat Non-neuronal Mechanisms Should Be Studied to Understand Epileptic Seizures?
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“Integrin expression is also increased during epileptogenesis and in pathologies associated with the development of epilepsy [87].”
BackgroundMaking tracks: microglia and the extracellular matrix
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“The type of contact microglia make with ECM components is influenced by extracellular cytokines such as TNFα and the immune-derived interferons IFN-α and IFN-γ, which in turn upregulate the expression of ECM receptor binding proteins including integrins [183–185].”
Hlavac, N., & VandeVord, P. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00099 · Cited by 26
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Gene expression profiles underlying aggressive behavior in the prefrontal cortex of cattle
Eusebi, P. G., Sevane, N., O’Rourke, T., Pizarro, M., Boeckx, C., & Dunner, S. (2021) · BMC Genomics · doi:10.1186/s12864-021-07505-5 · Cited by 24
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“However, other authors have reported the expression of a vast variety of integrin receptors in different structures of adult brain, including the heterodimeric αVβ3 and its subunits αV and β3, which may explain this uptake (37-39).”
BackgroundOsteopontin-metallothionein I/II interactions in experimental autoimmune encephalomyelitis.
Jakovac, H., Kezele, T. G., Šućurović, S., Mulac‐Jeričević, B., & Radošević-Stašić, B. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.03.020 · Cited by 24
“5A f) and that OPN activities were more related to its RGD-binding domain of OPN than to OPN-C fragment, but in spite of the fact that these findings are in line with current knowledge showing that binding of RGD fragment of many ECM proteins leads to activation and conformational change of integrin receptor and activ…”
Irisin-Associated Neuroprotective and Rehabilitative Strategies for Stroke
Huberman, M. A., d’Adesky, N., Niazi, Q. B., Pérez‐Pinzón, M. A., Bramlett, H. M., & Raval, A. P. (2021) · NeuroMolecular Medicine · doi:10.1007/s12017-021-08666-y · Cited by 23
“The αV/ β5 Integrin is expressed in many cells, including neuronal cells and has been a receptor target for neurological disorders for its role in neuroplasticity, cell survival, migration, and differentiation (Wu & Reddy, 2012).”
BackgroundCeruloplasmin Deamidation in Neurodegeneration: From Loss to Gain of Function
Zanardi, A., & Alessio, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020663 · Cited by 25
“In particular, considering that integrins recognized by isoDGR motif (such as αVβ3, αVβ5, αVβ6,αVβ8 and α5β1) [9,22,25] are widely expressed in the nervous system by both neuronal and glial cells [81], other cells out of CPEpiCs could also be targeted by the NGR-containing deamidated proteins.”
Backgroundαvβ3 Integrin Antagonists Enhance Chemotherapy Response in an Orthotopic Pancreatic Cancer Model
Coskun, M. D., Sudha, T., Bharali, D. J., Çelikler, S., Davis, P. J., & Mousa, S. A. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00095 · Cited by 22
“, 2010), rheumatoid arthritis related diseases (Wilder, 2002), and several neurological disorders (Wu and Reddy, 2012).”
BackgroundGohel, D., Zhang, P., Gupta, A. K., Li, Y., Chiang, C., Li, L., Hou, Y., Pieper, A. A., Cummings, J. L., & Cheng, F. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231391 · Cited by 25
“This signaling pathway is known to have pathophysiological role in neurodevelopment, plasticity, and central nervous system (CNS) diseases [51–53].”
BackgroundIncreased expression of copine VI in patients with refractory epilepsy and a rat model
Zhu, B., Zha, J., Long, Y., Hu, X., Chen, G., & Wang, X. (2015) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2015.11.041 · Cited by 21
“The A domain of copines mediates protein-protein interaction [8] and is similar to the von Willebrand A (VWA) domain found in integrins that are central to the pathophysiology of many brain diseases, such as epilepsy [28].”
MethodWu, X. Y., Muthuchamy, M., & Reddy, D. S. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00088 · Cited by 20
“…a connection between ECM and the intracellular focal adhesion complex (FAC) molecules including non-receptor tyrosine kinases (NRTKs) focal adhesion kinase (FAK) and Src, as well as cytoskeleton proteins, including talin and actin (Wu et al., 1998, 2001; Pinkstaff et al., 1999; Wu and Reddy, 2012).”
BackgroundSelf-citationTee, J. Y., Sutharsan, R., Fan, Y., & Mackay‐Sim, A. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.03.005 · Cited by 21
“All the integrin receptors detected in patient and control cells are commonly expressed by neurons and glia in the brain (Wu and Reddy, 2012), although the ECM composition of the developing and mature brain involves integrin-binding proteins (Jones et al., 2011; Katic et al., 2014), as well as…”
Kerrisk, M. E., & Koleske, A. J. (2013) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.07.018 · Cited by 21
Kiss, D., Ioja, E., Toth, I., Barany, Z., Jocsak, G., Bartha, T., Horvath, T., & Zsarnovszky, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19051440 · Cited by 18
“Additionally, the observed changes in transcription and translation rates in response to ZEN treatment might be induced by certain cellular adaptations to the applied experimental conditions and by the loss of tissue integrity, such as the absence of extracellular matrix proteins, integrins, and certain glycoproteins…”
BackgroundBrzdąk, P., Lebida, K., Wyroślak, M., & Mozrzymas, J. W. (2023) · Scientific Reports · doi:10.1038/s41598-023-31882-4 · Cited by 14
Yu, I., Chang, H., Chen, K., Lu, Y., Shy, H.-T., Chen, C.-Y., Lee, K., & Lee, L. (2019) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2019.00016 · Cited by 16
“Among these CTGF-binding proteins, integrins, lowdensity lipoprotein receptor-related protein 1 (LRP1), and vascular endothelial growth factor (VEGF) are known to modulate the development of oligodendrocyte in various aspects (Wu and Reddy, 2012; Auderset et al., 2016; Safina et al., 2016).”
BackgroundWu, X. Y., Muthuchamy, M., & Reddy, D. S. (2017) · Epilepsy Research · doi:10.1016/j.eplepsyres.2017.10.013 · Cited by 16
Self-citationde Araújo, M. A., Marques, T. E. B. S., Octacílio-Silva, S., Silva, C. L. D. A., Pereira, M. G. A. G., Peixoto-Santos, J. E., Kandratavicius, L., Leite, J. P., Garcia‐Cairasco, N., de Castro, O. W., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0163855 · Cited by 15
Neuroplasticidad: aspectos bioquímicos y neurofisiológicos
Garcés-Vieira, M. V., & Suárez-Escudero, J. C. (2014) · CES Medicina · Cited by 14
Bhuiyan, P., Sun, Z., Khan, M. A., Hossain, M. A., Rahman, M. H., & Qian, Y. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e25191 · Cited by 14
“Previously, it has been reported that SZ patient-derived cells are sensitive to ECM proteins that bind integrin receptors, thus resulting in increases in focal adhesion number and size in response to ECM proteins and alterations in cell shape and cytoskeleton [55].”
BackgroundCassone, C. G., Taylor, J. J., O’Brien, J. M., Williams, A., Yauk, C. L., Crump, D., & Kennedy, S. W. (2012) · Toxicological Sciences · doi:10.1093/toxsci/kfs219 · Cited by 13
“Integrin receptors and signaling 396 Integrins are transmembrane receptors essential to embryonic development and necessary 397 for neuronal cells to attach, spread, migrate and extend processes on extracellular matrix 398 molecules and mediate cell-cell and cell-matrix adhesion events (Wu and Reddy 2012).”
BackgroundEvolving Evidence of Calreticulin as a Pharmacological Target in Neurological Disorders
Kotian, V., Sarmah, D., Kaur, H., Kesharwani, R., Verma, G., Mounica, L., Veeresh, P., Kalia, K., Borah, A., Wang, X., et al. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00158 · Cited by 12
Jackson, T. C., Gorse, K., Herrmann, J. R., & Kochanek, P. M. (2021) · Molecular Neurobiology · doi:10.1007/s12035-020-02250-4 · Cited by 15
“There are at least 21 different integrin receptors in the brain, based on permutations in their subunit dimerization [37].”
BackgroundProteomic Response of the Brain to Hypoxic Stress in Marine Medaka Fish (Oryzias melastigma)
Lai, K. P., Tam, N. Y.-K., Wang, S. Y., Tse, W. K. F., Lin, X., Chan, T., Tong, Y., Zhang, J., Au, D. W. T., Wu, R. S. S., et al. (2021) · Frontiers in Marine Science · doi:10.3389/fmars.2021.618489 · Cited by 12
“Notably, aberrations in integrin signaling within the brain may impair the synaptic activity in brain disorders such as schizophrenia and epilepsy (Wu and Reddy, 2012).”
BackgroundThe Intricate Interplay: Microbial Metabolites and the Gut‐Liver‐Brain Axis in Parkinson's Disease
Kishanchand, D. K., A., A. K. K., Chandrababu, K., Philips, C. A., Sivan, U., & Chakrapani, P. S. B. (2025) · Journal of Neuroscience Research · doi:10.1002/jnr.70016 · Cited by 13
Gong, L., Zheng, Y., Liu, S., & Peng, Z. (2018) · Europe PMC (PubMed Central) · doi:10.22034/apjcp.2018.19.9.2493 · Cited by 11
“…in the formed MCA may promote the formation of focal adhesion complex, through its cytoplasmic region, to activate intracellular focal adhesion kinase (FAK) activation, leading to tumor cell invasion and metastasis (Sun et al., 2014; Li et al., 2017; Kukkurainen et al., 2014; Wu and Reddy, 2012).”
BackgroundBitiktas, S., Tan, B., Kavraal, Ş., Yousef, M., Bayar, Y., Dursun, N., & Süer, C. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23985 · Cited by 11
Poormoghadam, D., Almasi, A., Ashrafizadeh, M., Vishkaei, A. S., Rezayat, S. M., & Tavakol, S. (2020) · Nanotechnology · doi:10.1088/1361-6528/ab8d6b · Cited by 10
Role of dynamin 2 in the disassembly of focal adhesions
Briñas, L., Vassilopoulos, S., Bonne, G., Guicheney, P., & Bitoun, M. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1040-2 · Cited by 15
“On the other hand, integrin-based adhesion sites play important roles in the regulation of cell surface receptor, neurotransmitter receptors and calcium signalling in neurons [59], several processes potentially impaired by DNM2 mutation.”
BackgroundSelective Integrin α5β1 Targeting through Spatially Constrained Multivalent DNA-Based Nanoparticles
Kurisinkal, E. E., Caroprese, V., Koga, M. M., Morzy, D., & Bastings, M. M. C. (2022) · Molecules · doi:10.3390/molecules27154968 · Cited by 10
“The integrin α5β1 has been implicated in several diseases, ranging from cancer, inflammation [11], respiratory diseases [12], neurological disorders [13] and viruses, including SARS-CoV-2 [14], besides being engaged in cell adhesion [15].”
BackgroundLicheri, V., & Brigman, J. L. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.753537 · Cited by 11
“Several integrin α and β subunits are highly expressed in growth cones and synapses (Wu and Reddy, 2012; Park and Goda, 2016), and it is well established their role in building and maintain synaptic structure during the phases of the development (Benson et al.”
BackgroundCo-Expression Analysis of microRNAs and Proteins in Brain of Alzheimer’s Disease Patients
Watson, C. N., Begum, G., Ashman, E., Thorn, D., Yakoub, K. M., Hariri, M. A., Nehme, A., Mondello, S., Kobeissy, F. H., Belli, A., et al. (2022) · Cells · doi:10.3390/cells11010163 · Cited by 12
“hsamiR-30e-5p and Integrin beta-1 (ITGB1), a receptor for collagen, is another interaction, and it was suggested to undergo plasticity through interactions with ECM proteins, modulating ion channels, intracellular Ca2+ and protein kinases signalling, and reorganization of cytoskeletal filaments [47].”
BackgroundEnhanced glaucomatous damage accompanied by glial response in a new multifactorial mouse model
Reinehr, S., Girbig, R. M., Schulte, K. K., Theile, J., Asaad, M. A., Fuchshofer, R., Dick, H. B., & Joachim, S. C. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1017076 · Cited by 10
Yasodharababu, M., & Nair, A. K. (2020) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-020-00615-2 · Cited by 10
Advances in Polymer Micelles for Cancer Therapy: From Conventional to Smart Delivery Systems
Bryaskova, R. G., Staykov, K., & Ganchev, D. (2026) · Pharmaceutics · doi:10.3390/pharmaceutics18020177 · Cited by 10
Suresh, N. T., Vimina, E. R., & Krishnakumar, U. (2020) · Computational Biology and Chemistry · doi:10.1016/j.compbiolchem.2020.107323 · Cited by 9
Sim, H., Seo, J., Kim, J., Oh, M., Lee, J., Baek, A., Lee, S.-Y., Chung, S., Son, M., Chae, J., et al. (2020) · Life · doi:10.3390/life10120331 · Cited by 9
“As integrin dysfunction is involved in the pathogenesis of several disease states, many studies have targeted them for studying neurodegenerative diseases [34,35].”
Background
Metadata
- Authors
- Wu, X., & Reddy, D. S.
- Affiliations
- Texas A&M Health Science Center (US)
- Corresponding author
- Reddy, Doodipala Samba
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 134
- Issue
- 1
- Pages
- 68-81
- ISSN
- 0163-7258 (ISSN-L)
- PMC
- PMC3288359
- OpenAlex
- W2015445832
- Cited by
- 175
- References
- 202
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 12 · 2023: 16 · 2022: 12 · 2021: 17 · 2020: 12 · 2019: 21 · 2018: 14 · 2017: 5 · 2016: 10 · 2015: 5 · 2014: 8 · 2013: 8 · 2012: 4
- FWCI
- 0.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS051398, NS051398)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- integrins, neuroplasticity, neurological disorders, extracellular matrix, cell-cell adhesion, cell-matrix adhesion, integrin clustering, epilepsy, traumatic brain injury, seizures, therapeutic target, drug delivery, cytoskeletal remodeling, calcium signaling, protein kinase signaling
- MeSH terms
- Animals, Brain Diseases, Humans, Integrins
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