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Matrix metalloproteinases in autism spectrum disorders
Journal of Molecular Psychiatryvolume 1, Article number: 16 (2013)
Autism Spectrum Disorders (ASD) are group of developmental disabilities with a complex neurobiological basis including putative changes in the immune system. They are characterized by pervasive qualitative abnormalities in social interactions, communication, and stereotyped behaviour. Matrix metalloproteinases (MMPs) represent a group of proteases which play an important role in neuroinflammation and neurodevelopment. Therefore, they possibly have a crucial function in the etiopathology of ASD. In this review, we summarize the plausibility of the hypothesis that MMPs are involved in the neuropathology of ASD. Possible pathways through which MMPs can contribute to the pathogenesis of ASD are discussed including neuroinflammatory mechanisms inclusive of mediating neuropathological effects of infections, the associations between MMPs and other biomarkers such as cytokines, chemokines and neurotrophic factors. Despite sufficient evidence for such an involvement of MMPs in the neuropathology of ASD, they have not yet been extensively studied in this context. Thus, further research in this field is not only urgently needed but also very promising and may also lead to new therapeutic approaches.
Matrix metalloproteinases (MMPs), discovered back in 1962, are a family of at least 28 endopeptidases. They encompass a large family of proteases and share many similarities in their structure, regulation and function . In their active form, MMPs play a number of important roles not only in physiological conditions but also in pathological states . They are essential for various physiological processes such as embryonic development, morphogenesis and remodelling. Furthermore, they have been implicated in a number of key pathologic processes including inflammation, fibrosis, arthritis and cancer .
Additionally, MMPs play a crucial role in the development of the central nervous system (CNS) and neurogenesis as well as during phases of neuroinflammation [2, 3], a frequently reported finding in children with Autism Spectrum Disorders (ASD) .
Autism spectrum disorders (ASD), or pervasive developmental disorders (PDD), as termed in the International Classification of Diseases, 10th version , refer to a group of heterogeneous neurodevelopmental disorders characterized by qualitative impairments in social interaction, communication and repetitive stereotypic behaviour [6, 7]. While accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD , no definitive biologic screening or diagnostic tools have been universally accepted, and the diagnostic standards are still based on behavioural criteria .
This review first introduces briefly members of the MMPs and their biochemistry. This is followed by a short description of their physiological functions within CNS as well as their involvement in pathological states. The review focuses mainly on the potential pathways through which MMP’s can contribute to the etiopathology of ASD.
The structure and biochemistry of MMPs
MMPs along with the ADAMs (A Disintegrin And Metalloproteinase) and the ADAMTs (A Disintegrin And Metalloproteinase with Thrombospondin Motifs) are subgroups of the larger metzincin superfamily  that are collectively able to process and degrade various extracellular matrix (ECM) proteins. Based on their protein structure, MMPs are divided into four groups which include collagenases (such as MMP-1), stromelysins (MMP-3), gelatinases (MMP-2, MMP-7 and MMP-9), and membrane type metalloproteinases (MT-MMPs) such as (MMP-14) .
While MMPs were initially described to be the products macrophages and neutrophils acting on collagen, they are now known to be produced by different tissues and cell types, including osteoblasts, human umbilical vein endothelial cells, smooth muscle cells and keratinocytes . They often bind with heparin sulphate glycosaminoglycans on the cell surface and have wide range of substrates .
The regulation of MMPs is complex starting at gene transcription, posttranslational activation of zymogens, and endogenous inhibition . The synthesis and secretion of MMPs take place in inactive forms which are later activated by the loss of a 10-kDa propeptide either intracellularly or extracellularly. The activity of MMPs is balanced by the endogenous tissue inhibitors of metalloproteinases (TIMPs) and by α2-macroglobulin. The resulting equilibrium between production, activation, and inhibition prevents excessive proteolysis or inhibition [2, 10].
MMPs in the CNS
MMPs play an important role in the development of the CNS as well as during pathological periods of inflammation and injury. Substrates of MMPs have important functions in normal CNS development during synaptogenesis, synaptic plasticity, and long-term potentiation (LTP) . Several animal studies have documented the presence of different MMPs such as MMP-9 and MMP-2 in the brain [2, 13]. MMPs are mainly secreted by astrocytes and microglia within the CNS due to different triggers .
Alteration of MMPs expression has been detected in the nervous system in response to injury or neurological disease [15, 16]. MMPs have the ability to mediate the disruption of the blood brain barrier (BBB) by degrading the tight junctions’ proteins and basal lamina proteins, thereby leading to BBB leakage, leukocyte infiltration, brain edema, and hemorrhage. Furthermore, they regulate ECM protein destruction, remodelling and tissue inflammation in response to oxidative stress . Additionally, several reports have illustrated MMPs involvement in wide range of neurological pathologies such meningitis , multiple sclerosis , Alzheimer’s disease , inflammatory myopathies  and tumors of the CNS such as glioma .
Possible role of MMPs in the etiopathology of ASD
The neurobiological basis of ASD is complex, and several lines of research suggest that both genetic and envir-onmental factors contribute etiologically to ASD [22, 23]. Despite the extensive ongoing research, convergence towards a universal molecular pathway is still lacking, and ASD is still considered to have an idiopathic etiology in many individuals . Although MMPs have been extensively investigated in several somatic and psychiatric disorders [10, 24], their role in the etiopathology of ASD have been less extensively examined. Most of the research in this field has been targeting MMPs levels in individuals with Fragile-X Syndrome (FXS) , a disorder where at least 30% of patients have features of ASD . Several animal models of FXS have reported elevated levels of MMPs in the CNS . This drove the main interest in this area was targeted toward Minocycline, an antibiotic which is widely used to treat acne and other skin infections but also inhibits matrix metalloproteinase (MMP)-9 . Although the application of this drug to FXS patient in several clinical trials have revealed positive improvements in language, attention and behavioural improvements, research in this area is still ongoing .
Interestingly, in a recent study by Abdallah et al., , amniotic fluid samples for 331 ASD cases and 698 frequency-matched controls were analyzed for levels of MMP-9 along with other biomarkers utilizing a Danish historic birth cohort and Danish nationwide health registers Our results showed elevated levels of MMP-9 in ASD cases compared with controls and this was unrelated to FXS.
Contribution of MMPs to the etiopathology of ASD is biologically plausible through direct and indirect pathways which are not necessarily mutually exclusive. Several studies have reported disrupted synaptic pathways in some cases of ASD  along with abnormal formation of neuronal connections or elimination of inappropriate connections . Besides, anomalies of brain structure have repeatedly been reported in cases with ASD .
MMPs play important roles in neuronal development and neuroplasticity . They have also important functions in reactive synaptogenesis following brain injury . Interestingly, several neuronal activity altered genes associated with ASD such as those encoding Neurexin (NRXN1) and Neuroligin (NLGN3) are processed by MMPs. Furthermore, elevated levels of MMPs can induce hyperplasticity state within the CNS that eventually leads to ASD, fitting well within the hyperreactivity/hyperplasticity model of the disease . It is not clear though whether MMPs act directly or as an epiphenomenon to lead ultimately to ASD. This sheds the light on the potential role of MMPs in modulating neuroplasticity and neurogenesis indirectly through interaction with molecules such as neuroligins, integrins and growth factors .
MMPs can activate several neurotrophic factors (NFs), such as Brain-derived neurotrophic factor (BDNF), through cleavage processes of their proforms which can ultimately regulate neuronal survival, development, and synaptic plasticity .
Theoretically speaking, MMPs can also contribute to ASD pathology, on one hand, through inducing a neuroinflammatory state or through disruption of the BBB leaving the normally protected milieu of the CNS more vulnerable to the systemic circulation . On the other hand, MMPs have also the ability to act through different inflammatory markers associated with ASD pathology through their proteolytic activity. Such markers include cytokines, chemokines, and reactive oxygen species (ROS) [37, 38].
MMPs have the ability to regulate various inflammatory processes at different levels including epithelial repair, defence mechanisms against microorganisms and through modulatory effects on cytokines and chemokines . Furthermore, elevated levels of MMPs were reported in Experimental Allergic Encephalomyelitis (EAE), an animal model of a monophasic inflammatory demyelinating illness associated with ASD and other neuropsychiatric diseases. Interestingly, applying MMPs inhibitors has also showed antinflammatory effects . Given that neuroimmune factors can directly affect brain development and that neuroinflammation can be a critical pathogenic factor in the development of ASD , MMPs can serve as important candidates to better understand the underlying neurodevelopmental pathology in ASD.
The triad of infections, ASD and MMPs is of special importance. Several studies have reported associations between infections and ASD. Such associations were proposed as early as 1963, with Dr. Krevelen reporting congenital rubella infection in a patient with infantile autism . Both Congenital infections [42–44] and postnatal childhood infections [45, 46] were associated with high rate of ASD. On the other arm of the triad is the association between infections and MMPs. Elevated levels of MMPs (specifically MMP-1) were found associated with bacterial meningitis  and were correlated with cerebral injury and infection severity during infection. Also, there is an increased ROS-induced activity of MMPs during viral infections as a result of intracellular signalling by virion components or cytotoxic effects of viral non-structural proteins . Probably, the direct contribution of infections to the rising ASD prevalence is limited . However, their role triggering an inflammatory state is rather important . Taken together, it is possible that MMPs can intermediate the neuropathological effects of infections (and probably other environmental insults) which eventually contribute to the development of ASD.
There is also growing evidence regarding the important role of cytokines and chemokines in mediating inflammatory effects on the neurodevelopmental trajectory in autism and other psychiatric disorders such as schizo-phrenia . MMPs can regulate inflammatory response through their modulatory effects on cytokines and chemokines . Accumulating evidence shows that MMPs can either promote or repress inflammation through proteolytic processing of inflammatory cytokines and chemokines . For example, MMPs have the ability to amplify inflammatory response through activating cytokines such as Tumor necrosis factors α (TNF-α), Interleukin 1β (IL-1β) and wide range of chemokines. Elevated levels of TNF- α in amniotic fluid  cerebrospinal fluid , peripheral blood mononuclear cells [53, 54], whole blood samples  and post mortem brain tissue of autistic individuals  were repeatedly reported. Similar finding were also reported for IL-1 [57, 58].
MMPs have also the ability through their cleavage mechanisms and proteolytic processing to regulate chemokines gradient, and therefore, control the influx of leukocytes . Chemokines have been repeatedly reported to be associated with ASD . For example, we reported recently elevated levels of monocyte chemotactic protein-1 (MCP-1) (a CC chemokine encoded on human chromosome 17) in amniotic fluid samples of cases that developed ASD later in life . Interestingly chemokines share overlapping pathways with MMPs through which they contribute to the neuropathology of ASD. The role of some chemokines (such as MCP-1) in neuroinflammation has been well established using the animal model of EAE where a positive correlation between the expression and the degree of inflammation in the CNS was reported . Furthermore, this chemokine can act similarly to MMPs and induce BBB breakdown .
Taken together, MMPs can contribute to the etiopathology of ASD through several pathways which are not necessarily mutually exclusive. MMPs can modulate neuroplasticity and neurogenesis and contribute to a hyperplasticity state associated with ASD. Their pathologic proteolytic effects on the BBB can also leave the CNS vulnerable to the systemic circulation in critical developmental periods. Furthermore, MMPs can hinder neurodevelopment through inducing neuroinflammatory state within the CNS and through their proteolytic effects on NFs, cytokines and chemokines.
MMPs encompass a large family of proteases that share many similarities in their structure, regulation and function. These enzymes play crucial role not only in the normal development of the central nervous system but also in a number of key pathologic processes including inflammation, fibrosis, arthritis and cancer. Contribution of MMPs to the etiopathology of ASD is biologically plausible through direct and indirect pathways that are not necessarily mutually exclusive. This includes their role in neuroinflammation, BBB disruption and their modula-tory enzymatic effects on key biomarkers such as cytokines, chemokines and NFs. While MMPs have been extensively studied in several pathologies, their role in ASD was less extensively examined. In this review we presented the current evidence of MMPs contribution to ASD pathology. Despite the biologic plausibility, further research in this area including examining levels of MMPs in different stages during pregnancy and after birth is needed to identify their pattern in ASD and their associations with other markers such as cytokines and NFs.
A disintegrin and metalloproteinases
A disintegrin and metalloproteinase with thrombospondin motifs
Autism spectrum disorders
Brain-derived neurotrophic factor
Central nervous system
Experimental allergic encephalomyelitis
Fragile x syndrome
Reactive oxygen species.
Peng W, Yan J, Wan Y, Wang B B, Tao J, Yang G, Pan H, J W: Matrix metalloproteinases: a review of their structure and role in systemic sclerosis. J Clin Immunol 2012, 32: 1409–1414.
Rosenberg GA: Matrix metalloproteinases in neuroinflammation. Glia 2002, 39: 279–291.
Ethell IM, Ethell DW: Matrix metalloproteinases in brain development and remodeling: Synaptic functions and targets. J Neurosci Res 2007, 85: 2813–2823.
Pardo-Villamizar CA: Can Neuroinflammation Influence the Development of Autism Spectrum Disorders? In Autism: Current Theories and Evidence (Current Clinical Neurology). Edited by: Zimmerman AW. Totowa: Humana Press; 2008:329–346.
WHO: The ICD-10 Classification of Mental and Behavioural Disorders. In International Statistical Classification of Diseases and Related Health Problems 10th Revision. Geneva, Switzerland: WHO - DIMDI; 2010.
APA: Diagnostic and Statistical Manual of Mental Disorders. 4th, Text Revision edn. Washington, DC: American Psychiatric Publishing, Inc; 2000.
Myers SM, Challman TD: Autism Spectrum Disorders. In Developmental and Behavioral Pediatrics. First edition. Edited by: Voigt RG. Elk Grove Village, Illinois: American Academy of Pediatrics; 2010:249–291.
Onore C, Careaga M, Ashwood P: The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun 2012, 383: 392.
Stöcker W, Bode W: Structural features of a superfamily of zinc-endopeptidases: the metzincins. Curr Opin Struct Biol 1995, 5: 383–390.
Amălinei C, Căruntu I-d, Giuşcă SE, Bălan RA: Matrix metalloproteinases involvement in pathologic conditions. Rom J Morphol Embryol 2010, 51: 215–228.
Karthikeyan VJ, Lane DA, Beevers DG, Lip GYH, Blann AD: Matrix metalloproteinases and their tissue inhibitors in hypertension-related pregnancy complications. J Hum Hypertens 2013, 27: 72–78.
Galis ZS, Khatri JJ: Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002, 90: 251–262.
Yong VW: Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 2005, 6: 931–944.
Rosenberg GA, Cunningham LA, Wallace J, Alexander S, Estrada EY, Grossetete M, Razhagi A, Miller K, Gearing A: Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res 2001, 893: 104–112.
Yong VW, Power C, Forsyth P, Edwards DR: Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2001, 2: 502–511.
Abdallah MW, Pearce BD, Larsen N, Greaves-Lord K, Nørgaard-Pedersen B, Hougaard DM, Mortensen EL, Grove J: Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study. Autism Res 2012, 5: 428–433.
Swarnakar S, Paul S, Singh LP, Reiter RJ: Matrix metalloproteinases in health and disease: regulation by melatonin. J Pineal Res 2011, 50: 8–20.
Green JA, Thi Hong Chau T, Farrar JJ, Friedland JS, Thwaites GE: CNS infection, CSF matrix metalloproteinase concentrations, and clinical/laboratory features. Neurology 2011, 76: 577–579.
Özenci V, Kouwenhoven M, Teleshova N, Pashenkov M, Fredrikson S, Link H: Multiple sclerosis: pro- and anti-inflammatory cytokines and metalloproteinases are affected differentially by treatment with IFN-β. J Neuroimmunol 2000, 108: 236–243.
Wee Yong V, Forsyth PA, Bell R, Krekoski CA, Edwards DR: Matrix metalloproteinases and diseases of the CNS. Trends Neurosci 1998, 21: 75–80.
Uhm JH, Dooley NP, Villemure JG, Yong VW: Mechanisms of glioma invasion: role of matrix-metalloproteinases. Can J Neurol Sci 1997, 24: 3–15.
Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether JK, Levy SE, Mandell DS, Miller LA, Pinto-Martin J, Reaven J, et al.: The epidemiology of autism spectrum disorders. Annu Rev Public Health 2007, 28: 235–258.
Hertz-Picciotto I, Croen LA, Hansen R, Jones CR, van de Water J, Pessah IN: The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism. Environ Health Perspect 2006, 114: 1119–1125.
Baker AH, Edwards DR, Murphy G: Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 2002, 115: 3719–3727.
Krueger DD, Bear MF: Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu Rev Med 2011, 62: 411–429.
Gillberg C, Billstedt E: Autism and Asperger syndrome: coexistence with other clinical disorders. Acta Psychiatr Scand 2000, 102: 321–330.
Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, Ethell IM: Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet 2009, 46: 94–102.
Paribello C, Tao L, Folino A, Berry-Kravis E, Tranfaglia M, Ethell I, Ethell D: Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol 2010, 10: 91.
Hagerman R, Hoem G, Hagerman P: Fragile X and autism: Intertwined at the molecular level leading to targeted treatments. Molecular Autism 2010, 1: 1–14.
Betancur C, Sakurai T, Buxbaum JD: The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders. Trends Neurosci 2009, 32: 402–412.
Møller AR: Plasticity diseases. Neurol Res 2009, 31: 1023–1030.
Nickl-Jockschat T, Habel U, Maria Michel T, Manning J, Laird AR, Fox PT, Schneider F, Eickhoff SB: Brain structure anomalies in autism spectrum disorder—a meta-analysis of VBM studies using anatomic likelihood estimation. Hum Brain Mapp 2011, 33: 1470–1489.
Fujioka H, Dairyo Y, Yasunaga K-i, Emoto K: Neural functions of matrix metalloproteinases: plasticity, neurogenesis, and disease. Biochem Res Int 2012, 2012: 8.
Markram K, Markram H: The Intense World Theory - a unifying theory of the neurobiology of autism. Front Hum Neurosci 2010, 4: 224.
Huang EJ, Reichardt LF: NEUROTROPHINS: roles in neuronal development and function*. Annu Rev Neurosci 2001, 24: 677–736.
Seo JH, Guo S, Lok J, Navaratna D, Whalen MJ, Kim K-W, Lo EH: Neurovascular matrix metalloproteinases and the blood–brain barrier. Curr Pharm Des 2012, 18: 3645–3648.
Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG: The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol 2010, 48: 504–511.
Yoo HG, Shin BA, Park JS, Lee KH, Chay KO, Yang SY, Ahn BW, Jung YD: IL-1β induces MMP-9 via reactive oxygen species and NF-κB in murine macrophage RAW 264.7 cells. Biochem Biophys Res Commun 2002, 298: 251–256.
Parks WC, Wilson CL, Lopez-Boado YS: Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 2004, 4: 617–629.
Gijbels K, Galardy R, Steinman L: Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases. J Clin Investig 1994, 94: 2177.
Rimland B: Infantile autism: the syndrome and its implications for a neural theory of behavior. New York: Appleton-Century-Crofts; 1964.
Patterson PH: Infections and Behaviour. In Infectious Behavior: Brain-Immune Connections in Autism, Schizophrenia, and Depression. Cambridge, MA: The MIT Press; 2011:61–72.
Yamashita Y, Fujimoto C, Nakajima E, Isagai T, Matsuishi T: Possible association between congenital cytomegalovirus infection and autistic disorder. J Autism Dev Disord 2003, 33: 455–459.
Libbey JE, Sweeten TL, McMahon WM, Fujinami RS: Autistic disorder and viral infections. J Neurovirol 2005, 11: 1–10.
Atladottir HO, Thorsen P, Schendel DE, Ostergaard L, Lemcke S, Parner ET: Association of hospitalization for infection in childhood with diagnosis of autism spectrum disorders: a Danish cohort study. Arch Pediatr Adolesc Med 2010, 164: 470–477.
Abdallah MW, Hougaard DM, Nørgaard-Pedersen B, Grove J, Bonefeld-Jørgensen EC, Mortensen EL: Infections during pregnancy and after birth, and the risk of autism spectrum disorders: A register-based study utilizing a Danish historic birth cohort. Turk Psikiyatri Derg 2012, 23: 229–236.
Spindler KR, Hsu T-H: Viral disruption of the blood–brain barrier. Trends Microbiol 2012, 20: 282–290.
Atladottir HO, Thorsen P, Schendel D, Ostergaard L, Abdallah M, Lemcke S, Parner E: Maternal Infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord 2010, 40: 1423–1430.
Patterson PH: Maternal infection and immune involvement in autism. Trends Mol Med 2011, 17: 389–394.
Deverman BE, Patterson PH: Cytokines and CNS development. Neuron 2009, 64: 61–78.
Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM: Amniotic fluid inflammatory cytokines: potential markers of immunologic dysfunction in autism spectrum disorders. World J Biol Psychiatry in press
Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M: Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol 2007, 36: 361–365.
Jyonouchi H, Geng L, Ruby A, Reddy C, Zimmerman-Bier B: Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders. J Pediatr 2005, 146: 605–610.
Jyonouchi H, Sun S, Le H: Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 2001, 120: 170–179.
Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M: Activation of the inflammatory response system in autism. Neuropsychobiology 2002, 45: 1–6.
Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M: Elevated immune response in the brain of autistic patients. J Neuroimmunol 2009, 207: 111–116.
Ashdown H, Dumont Y, Ng M, Poole S, Boksa P, Luheshi GN: The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia. Mol Psychiatry 2006, 11: 47–55.
Parker-Athill EC, Tan J: Maternal immune activation and autism spectrum disorder: interleukin-6 signaling as a key mechanistic pathway. Neurosignals 2010, 18: 113–128.
Manicone AM, McGuire JK: Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol 2008, 19: 34–41.
Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J: Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J Neuroimmunol 2011, 232: 196–199.
Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM: Amniotic fluid chemokines and autism spectrum disorders: An exploratory study utilizing a Danish Historic Birth Cohort. Brain Behav Immun 2012, 26: 170–176.
Mahad DJ, Ransohoff RM: The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Semin Immunol 2003, 15: 23–32.
Stamatovic SM, Shakui P, Keep RF, Moore BB, Kunkel SL, Van Rooijen N, Andjelkovic AV: Monocyte chemoattractant protein-1 regulation of blood–brain barrier permeability. J Cereb Blood Flow Metab 2005, 25: 593–606.
The Authors thank Dipl-Ing Christoph Berger for his fruitful discussion.
The authors declare that they have no competing interests.
MWA collected the data, developed the design, wrote the manuscript, and produced final version of the manuscript. TMM participated in the design, interpretation of the studies and review of the manuscript. Both authors read and approved the final manuscript.