Neuroprotective effects of direct activation and transactivation of PDGFβ receptors

Abstract

Platelet-derived growth factor (PDGF) receptors are expressed throughout the body, including the central nervous system (CNS). Although the physiological role of PDGF receptors in the developed CNS is not fully characterized, PDGF signaling appears to provide neuroprotective effects against several neuronal insults. One of the best-characterized neuroprotective effects of PDGF type-β receptors is against human immunodeficiency virus (HIV) protein-induced neurotoxicity, with potential physiological relevance to HAD. PDGFβ receptors are also neuroprotective against glutamate excitotoxicity, which is associated with both stroke and neurodegenerative diseases, including Alzheimer’s disease. The neuroprotective effects of PDGFβ receptors occur both via direct activation by ligand (PDGF-BB), as well as by PDGFβ receptors activated downstream of G protein-coupled receptor signaling. In addition to the involvement of PDGF signaling in various pathologies and potential therapies, there is also an emerging body of evidence that PDGF may serve as a biomarker for neurological or psychiatric diseases.

Keywords

Platelet-derived growth factor receptor / serotonin / glutamate / transactivation

References

[1] Heldin CH,Ronnstrand L.Signal transduction via platelet-derived growth factor receptors..Biochim Biophys Acta1998;1378:F79-113

[2] Kazlauskas A.PDGFs and their receptors..Gene2017;614:1-7 PMCID:PMC6728141

[3] Heldin CH.Mechanism of action and in vivo role of platelet-derived growth factor..Physiol Rev1999;79:1283-316

[4] Sil S,Thangaraj A,Buch S.PDGF/PDGFR axis in the neural systems..Mol Aspects Med2018;62:63-74 PMCID:PMC6003857

[5] Williams BP,Alberta JA,Hwang GY.A PDGF-regulated immediate early gene response initiates neuronal differentiation in ventricular zone progenitor cells..Neuron1997;18:553-62

[6] Smits A,Westermark B,Heldin CH.Neurotrophic activity of platelet-derived growth factor (PDGF): rat neuronal cells possess functional PDGF beta-type receptors and respond to PDGF..Proc Natl Acad Sci U S A1991;88:8159-63 PMCID:PMC52466

[7] Beazely MA,Li H,Chen X.Platelet-derived growth factor selectively inhibits NR2B-containing N-methyl-D-aspartate receptors in CA1 hippocampal neurons..J Biol Chem2009;284:8054-63 PMCID:PMC2658099

[8] Yeh HJ,Wang YX,Snider WD.PDGF A-chain gene is expressed by mammalian neurons during development and in maturity..Cell1991;64:209-16

[9] Yeh HJ,Wang YX,Snider WD.Developmental expression of the platelet-derived growth factor alpha-receptor gene in mammalian central nervous system..Proc Natl Acad Sci U S A1993;90:1952-6 PMCID:PMC45998

[10] Paul G,Varrone A,Jerling M.Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patients..J Clin Invest2015;125:1339-46 PMCID:PMC4362250

[11] Papadopoulos N.The PDGF/PDGFR pathway as a drug target..Mol Aspects Med2018;62:75-88

[12] Ishii Y,Yamamoto S.Pathogenetic significance and possibility as a therapeutic target of platelet derived growth factor..Pathol Int2017;67:235-46

[13] Doble A.The role of excitotoxicity in neurodegenerative disease: implications for therapy..Pharmacol Ther1999;81:163-221

[14] Ghafouri M,Khalili K.HIV-1 associated dementia: symptoms and causes..Retrovirology2006;3:28 PMCID:PMC1513597

[15] Schouten J,Gisslen M,Portegies P.HIV-1 infection and cognitive impairment in the cART era: a review..AIDS2011;25:561-75

[16] Thomas SA.Anti-HIV drug distribution to the central nervous system..Curr Pharm Des2004;10:1313-24

[17] Lindl KA,Kolson DL.HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities..J Neuroimmune Pharmacol2010;5:294-309 PMCID:PMC2914283

[18] Bachis A.Brain-derived neurotrophic factor is neuroprotective against human immunodeficiency virus-1 envelope proteins..Ann N Y Acad Sci2005;1053:247-57

[19] Sanders VJ,Johnson RW.Fibroblast growth factor modulates HIV coreceptor CXCR4 expression by neural cells. HNRC Group..J Neurosci Res2000;59:671-9

[20] Malik S,Buch S.A growth factor attenuates HIV-1 Tat and morphine induced damage to human neurons: implication in HIV/AIDS-drug abuse cases..PLoS One2011;6:e18116 PMCID:PMC3063804

[21] Peng F,Callen S,Bokhari S.Platelet-derived growth factor protects neurons against gp120-mediated toxicity..J Neurovirol2008;14:62-72 PMCID:PMC2716012

[22] Peng F,Yao H,Williams R.Mechanisms of platelet-derived growth factor-mediated neuroprotection--implications in HIV dementia..Eur J Neurosci2008;28:1255-64 PMCID:PMC2716063

[23] Yao H,Dhillon N,Bokhari S.Involvement of TRPC channels in CCL2-mediated neuroprotection against tat toxicity..J Neurosci2009;29:1657-69 PMCID:PMC2768421

[24] Yao H,Niu F,Peng F.Yin and Yang of PDGF-mediated signaling pathway in the context of HIV infection and drug abuse..J Neuroimmune Pharmacol2014;9:161-7 PMCID:PMC3865168

[25] Zhu X,Peng F,Buch S.PDGF-mediated protection of SH-SY5Y cells against Tat toxin involves regulation of extracellular glutamate and intracellular calcium..Toxicol Appl Pharmacol2009;240:286-91 PMCID:PMC2753679

[26] Yao H,Yang L.Platelet-derived growth factor-BB restores human immunodeficiency virus Tat-cocaine-mediated impairment of neurogenesis: role of TRPC1 channels..J Neurosci2012;32:9835-47 PMCID:PMC3438664

[27] Funa K.The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system..J Neuroimmune Pharmacol2014;9:168-81 PMCID:PMC3955130

[28] Chao J,Yao H.Platelet-derived growth factor-BB restores HIV Tat -mediated impairment of neurogenesis: role of GSK-3beta/beta-catenin..J Neuroimmune Pharmacol2014;9:259-68 PMCID:PMC4183349

[29] Yang L,Hu G,Liao K.Mechanisms of platelet-derived growth factor-BB in restoring HIV tat-cocaine-mediated impairment of neuronal differentiation..Mol Neurobiol2016;53:6377-87 PMCID:PMC4870169

[30] Sato H,Yamamoto S,Takahashi Y.PDGFR-beta plays a key role in the ectopic migration of neuroblasts in cerebral stroke..Stem Cells2016;34:685-98

[31] Hu G,Liao K,Sil S.HIV-1 Tat-induced astrocytic extracellular vesicle miR-7 impairs synaptic architecture..J Neuroimmune Pharmacol2019; PMCID:PMC7008083

[32] Valenzuela CF,MacDonald JF,Frazier CJ.Platelet-derived growth factor induces a long-term inhibition of N-methyl-D-aspartate receptor function..J Biol Chem1996;271:16151-9

[33] Lei S,Xiong ZG,Valenzuela CF.Platelet-derived growth factor receptor-induced feed-forward inhibition of excitatory transmission between hippocampal pyramidal neurons..J Biol Chem1999;274:30617-23

[34] Beazely MA,MacDonald JF.Abelson tyrosine kinase links PDGFbeta receptor activation to cytoskeletal regulation of NMDA receptors in CA1 hippocampal neurons..Mol Brain2008;1:20 PMCID:PMC2651131

[35] Zheng LS,Zhao QL,Sasahara M.PDGF suppresses oxidative stress induced Ca2+ overload and calpain activation in neurons..Oxid Med Cell Longev2013;2013:367206 PMCID:PMC3886591

[36] Zheng L,Tokunaga A,Shen J.Neuroprotective effects of PDGF against oxidative stress and the signaling pathway involved..J Neurosci Res2010;88:1273-84

[37] Tseng HC.Platelet-derived growth factor-BB pretreatment attenuates excitotoxic death in cultured hippocampal neurons..Neurobiol Dis2005;19:77-83

[38] Sims KD,Robinson MB.Platelet-derived growth factor rapidly increases activity and cell surface expression of the EAAC1 subtype of glutamate transporter through activation of phosphatidylinositol 3-kinase..J Biol Chem2000;275:5228-37

[39] Krizman-Genda E,Zelenaia O.Evidence that Akt mediates platelet-derived growth factor-dependent increases in activity and surface expression of the neuronal glutamate transporter, EAAC1..Neuropharmacology2005;49:872-82

[40] Iihara K,Tsukahara T,Yanamoto H.Platelet-derived growth factor-BB, but not -AA, prevents delayed neuronal death after forebrain ischemia in rats..J Cereb Blood Flow Metab1997;17:1097-106

[41] Kawabe T,Matsuda S,Otsuda H.Platelet-derived growth factor prevents ischemia-induced neuronal injuries in vivo..Neurosci Res1997;29:335-43

[42] Sakata M,Hashimoto N,Tsukahara T.Induction of infarct tolerance by platelet-derived growth factor against reversible focal ischemia..Brain Res1998;784:250-5

[43] Egawa-Tsuzuki T,Tanaka N,Uramoto H.The PDGF B-chain is involved in the ontogenic susceptibility of the developing rat brain to NMDA toxicity..Exp Neurol2004;186:89-98

[44] Iihara K,Hashimoto N,Kikuchi H.Ischemia induces the expression of the platelet-derived growth factor-B chain in neurons and brain macrophages in vivo..J Cereb Blood Flow Metab1994;14:818-24

[45] Suzuki J,Ohno I,Nawata J.Immunohistochemical analysis of platelet-derived growth factor-B expression in myocardial tissues in hypertrophic cardiomyopathy..Cardiovasc Pathol1999;8:223-31

[46] Lee JC,Lee TK,Cho JH.Effects of ischemic preconditioning on PDGF-BB expression in the gerbil hippocampal CA1 region following transient cerebral ischemia..Mol Med Rep2017;16:1627-34 PMCID:PMC5562056

[47] Ohno M,Narumiya S,Yamano T.Expression of platelet-derived growth factor B-chain and beta-receptor in hypoxic/ischemic encephalopathy of neonatal rats..Neuroscience1999;90:643-51

[48] Krupinski J,Bujny T,Kumar P.A putative role for platelet-derived growth factor in angiogenesis and neuroprotection after ischemic stroke in humans..Stroke1997;28:564-73

[49] Ishii Y,Zheng L,Kawaguchi M.Mouse brains deficient in neuronal PDGF receptor-beta develop normally but are vulnerable to injury..J Neurochem2006;98:588-600

[50] Nikolakopoulou AM,Montagne A.Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-beta signaling..PLoS One2017;12:e0176225 PMCID:PMC5404855

[51] Lewandowski SA,Lawrence DA.Pharmacological targeting of the PDGF-CC signaling pathway for blood-brain barrier restoration in neurological disorders..Pharmacol Ther2016;167:108-19 PMCID:PMC5341142

[52] Shen J,Xu G,Hamashima T.PDGFR-beta as a positive regulator of tissue repair in a mouse model of focal cerebral ischemia..J Cereb Blood Flow Metab2012;32:353-67 PMCID:PMC3272602

[53] Shibahara T,Nakamura K,Yoshikawa Y.Pericyte-mediated tissue repair through PDGFRbeta promotes peri-infarct astrogliosis, oligodendrogenesis, and functional recovery after acute ischemic stroke..eNeuro2020;7: PMCID:PMC7070447

[54] Shen J,Zhu R,Ishii Y.PDGFR-beta restores blood-brain barrier functions in a mouse model of focal cerebral ischemia..J Cereb Blood Flow Metab2019;39:1501-15 PMCID:PMC6681529

[55] Niu F,Liao K.HIV Tat 101-mediated loss of pericytes at the blood-brain barrier involves PDGF-BB..Ther Targets Neurol Dis2015;2:e471 PMCID:PMC4444060

[56] Niu F,Zhang W,Buch S.Tat 101-mediated enhancement of brain pericyte migration involves platelet-derived growth factor subunit B homodimer: implications for human immunodeficiency virus-associated neurocognitive disorders..J Neurosci2014;34:11812-25 PMCID:PMC4145180

[57] Miners JS,Love S.Differing associations between Abeta accumulation, hypoperfusion, blood-brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer’s disease..J Cereb Blood Flow Metab2018;38:103-15 PMCID:PMC5757436

[58] Padel T,Boix J,Gaceb A.Platelet-derived growth factor-BB has neurorestorative effects and modulates the pericyte response in a partial 6-hydroxydopamine lesion mouse model of Parkinson’s disease..Neurobiol Dis2016;94:95-105

[59] Milesi S,Plaud C,Rousset MC.Redistribution of PDGFRbeta cells and NG2DsRed pericytes at the cerebrovasculature after status epilepticus..Neurobiol Dis2014;71:151-8 PMCID:PMC4179992

[60] Bethel-Brown C,Hu G.Platelet-derived growth factor (PDGF)-BB-mediated induction of monocyte chemoattractant protein 1 in human astrocytes: implications for HIV-associated neuroinflammation..J Neuroinflammation2012;9:262 PMCID:PMC3526410

[61] Jansson D,Rustenhoven J,Smyth LC.Interferon-gamma blocks signalling through PDGFRbeta in human brain pericytes..J Neuroinflammation2016;13:249 PMCID:PMC5031293

[62] Hardy JA.Alzheimer’s disease: the amyloid cascade hypothesis..Science1992;256:184-5

[63] Barroeta-Espar I,Perez-Nievas BG,Siao Tick Chong M.Distinct cytokine profiles in human brains resilient to Alzheimer’s pathology..Neurobiol Dis2019;121:327-37 PMCID:PMC6437670

[64] O’Brien RJ.Amyloid precursor protein processing and Alzheimer’s disease..Annu Rev Neurosci2011;34:185-204 PMCID:PMC3174086

[65] Kim C,Bang JH,Joo I.Amyloid precursor protein processing is separately regulated by protein kinase C and tyrosine kinase in human astrocytes..Neurosci Lett2002;324:185-8

[66] Gianni D,Bimonte M,Mercken L.Platelet-derived growth factor induces the beta-gamma-secretase-mediated cleavage of Alzheimer’s amyloid precursor protein through a Src-Rac-dependent pathway..J Biol Chem2003;278:9290-7

[67] Zambrano N,Bruni P,Telese F.Fe65 is not involved in the platelet-derived growth factor-induced processing of Alzheimer’s amyloid precursor protein, which activates its caspase-directed cleavage..J Biol Chem2004;279:16161-9

[68] Friedman R,Caflisch A.Amyloid aggregation on lipid bilayers and its impact on membrane permeability..J Mol Biol2009;387:407-15

[69] Xie L,Taddei K,Van Bronswijk W.Alzheimer’s beta-amyloid peptides compete for insulin binding to the insulin receptor..J Neurosci2002;22:RC221 PMCID:PMC6757630

[70] Minano-Molina AJ,Martin E,Fado R.Soluble oligomers of amyloid-beta peptide disrupt membrane trafficking of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor contributing to early synapse dysfunction..J Biol Chem2011;286:27311-21 PMCID:PMC3149325

[71] Liu H,Vasefi MS,Kruk JS.Amyloid-beta inhibits PDGFbeta receptor activation and prevents PDGF-BBInduced neuroprotection..Curr Alzheimer Res2018;15:618-27

[72] Vasefi MS,Heikkila JJ.5-Hydroxytryptamine type 7 receptor neuroprotection against NMDA-induced excitotoxicity is PDGFbeta receptor dependent..J Neurochem2013;125:26-36

[73] Paul G.Trophic factors for Parkinson’s disease: where are we and where do we go from here?.Eur J Neurosci2019;49:440-52

[74] Tome D,Campos FL.Role of neurotrophic factors in Parkinson’s disease..Curr Pharm Des2017;23:809-38

[75] Lue LF,Snyder NL,Walker DG.Converging mediators from immune and trophic pathways to identify Parkinson disease dementia..Neurol Neuroimmunol Neuroinflamm2016;3:e193 PMCID:PMC4733150

[76] Cabezas R,Gonzalez J,Barreto GE.PDGF-BB protects mitochondria from rotenone in T98G cells..Neurotox Res2015;27:355-67

[77] Cabezas R,Gonzalez-Sanmiguel J,Esquinas P.PDGF-BB preserves mitochondrial morphology, attenuates ROS production, and upregulates neuroglobin in an astrocytic model under rotenone insult..Mol Neurobiol2018;55:3085-95

[78] Miyazaki I.Therapeutic strategy of targeting astrocytes for neuroprotection in Parkinson’s disease..Curr Pharm Des2017;23:4936-47

[79] Cabezas R,Hidalgo-Lanussa O,Ashrad GM.Growth factors and neuroglobin in astrocyte protection against neurodegeneration and oxidative stress..Mol Neurobiol2019;56:2339-51

[80] Okada T,Badawy SMM,Kajimoto T.Impairment of PDGF-induced chemotaxis by extracellular alpha-synuclein through selective inhibition of Rac1 activation..Sci Rep2016;6:37810 PMCID:PMC5122898

[81] Tang Z,Lee C,Kumar A.Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3beta phosphorylation..J Exp Med2010;207:867-80 PMCID:PMC2856029

[82] Shah BH.GPCR-mediated transactivation of RTKs in the CNS: mechanisms and consequences..Trends Neurosci2004;27:48-53

[83] Kruk JS,Grimberg N,Beazely MA.Transactivation of receptor tyrosine kinases by dopamine receptors. Dopamine Receptor Technologies.2015;New York, NYSpringer New York211-27

[84] Gill RS,Sum CS,Clark SD.The dopamine D4 receptor activates intracellular platelet-derived growth factor receptor beta to stimulate ERK1/2..Cell Signal2010;22:285-90

[85] Heeneman S,Saito Y,Berk BC.Angiotensin II induces transactivation of two different populations of the platelet-derived growth factor beta receptor. Key role for the p66 adaptor protein Shc..J Biol Chem2000;275:15926-32

[86] Shen Y,Metcalf MA,Hamblin MW.Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype..J Biol Chem1993;268:18200-4

[87] Thomas DR.5-HT7 receptors..Curr Drug Targets CNS Neurol Disord2004;3:81-90

[88] Speranza L,Volpicelli F,Lacivita E.Serotonin 5-HT7 receptor increases the density of dendritic spines and facilitates synaptogenesis in forebrain neurons..J Neurochem2017;141:647-61

[89] Vasefi MS,Liu H,Beazely MA.Activation of 5-HT7 receptors increases neuronal platelet-derived growth factor beta receptor expression..Neurosci Lett2012;511:65-9

[90] Samarajeewa A,Vasefi MS,Gondora N.5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation..Front Behav Neurosci2014;8:391 PMCID:PMC4224134

[91] Kotecha SA,Jackson MF,Orser BA.A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission..Neuron2002;35:1111-22

[92] Vasefi MS,Li J,Heikkila JJ.Acute 5-HT7 receptor activation increases NMDA-evoked currents and differentially alters NMDA receptor subunit phosphorylation and trafficking in hippocampal neurons..Mol Brain2013;6:24 PMCID:PMC3661375

[93] Kanki H,Matsumura S,Yukami T.beta-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-beta in stroke..Cell Death Dis2019;10:100 PMCID:PMC6361911

[94] Abassi M,Nakigozi G,Kong X.Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda..J Neurovirol2017;23:369-75 PMCID:PMC5441942

[95] Jung KH,Lee ST,Jeon D.Multipotent PDGFRbeta-expressing cells in the circulation of stroke patients..Neurobiol Dis2011;41:489-97

[96] Bjorkqvist M,Minthon L.Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer’s disease..PLoS One2012;7:e29868 PMCID:PMC3261152

[97] Rocha de Paula M,Berretta R.Differences in abundances of cell-signalling proteins in blood reveal novel biomarkers for early detection of clinical Alzheimer’s disease..PLoS One2011;6:e17481 PMCID:PMC3063784

[98] Hu WT,Arnold SE,Clark CM.Novel CSF biomarkers for Alzheimer’s disease and mild cognitive impairment..Acta Neuropathol2010;119:669-78 PMCID:PMC2880811

[99] Mahlknecht P,Sprenger F,Hametner E.An antibody microarray analysis of serum cytokines in neurodegenerative Parkinsonian syndromes..Proteome Sci2012;10:71 PMCID:PMC3539904

[100] Furukawa T,Fujita K,Shimizu F.CSF cytokine profile distinguishes multifocal motor neuropathy from progressive muscular atrophy..Neurol Neuroimmunol Neuroinflamm2015;2:e138 PMCID:PMC4529282

[101] Frydecka D,Lubeiro A,Stanczykiewicz B.Profiling inflammatory signatures of schizophrenia: A cross-sectional and meta-analysis study..Brain Behav Immun2018;71:28-36

[102] Zai G,Tiwari A,Braithwaite J.Weak association of the platelet-derived growth factor beta (PDGFB) and PDGF receptor beta (PDGFRB) genes with schizophrenia and schizoaffective disorder..World J Biol Psychiatry2011;12:127-33

[103] Vanlandewijck M,Andaloussi Mae M,Hornemann S.Functional characterization of germline mutations in PDGFB and PDGFRB in primary familial brain calcification..PLoS One2015;10:e0143407 PMCID:PMC4658112

[104] Nicolas G,de Lemos RR,Guillin O.Brain calcification process and phenotypes according to age and sex: lessons from SLC20A2, PDGFB, and PDGFRB mutation carriers..Am J Med Genet B Neuropsychiatr Genet2015;168:586-94