Microglial Activation in Young Adults With Autism Spectrum Disorder

Suzuki, Katsuaki; Sugihara, Genichi; Ouchi, Yasuomi; Nakamura, Kazuhiko; Futatsubashi, Masami; Takebayashi, Kiyokazu; Yoshihara, Yujiro; Omata, Kei; Matsumoto, Kaori; Tsuchiya, Kenji J.; Iwata, Yasuhide; Tsujii, Masatsugu; Sugiyama, Tomoya; Mori, Norio

doi:10.1001/jamapsychiatry.2013.272

Cited by 415 publications

(316 citation statements)

References 66 publications

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“…Microglia, the highly plastic resident immune cells of the brain (6,7), have been shown to be activated in the brains of patients with ASD (8)(9)(10)(11). Microglia activation and proliferation could lead to focal inflammation of the brain and "choking" of normal synaptic connectivity (12,13). Microglia express membrane receptors for several neuropeptides, allowing them to communicate with neurons, astrocytes (14), and mast cells (15), known to be involved in allergic and inflammatory processes (16).…”

mentioning

confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

104

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We had reported elevated serum levels of the peptide neurotensin (NT) in children with autism spectrum disorders (ASD). Here, we show that NT stimulates primary human microglia, the resident immune cells of the brain, and the immortalized cell line of human microglia-SV40. NT (10 nM) increases the gene expression and release (P < 0.001) of the proinflammatory cytokine IL-1β and chemokine (C-X-C motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine and chemokine gene expression and release from human microglia. Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be translocated from the cytoplasm to the cell surface, and to be secreted extracellularly. Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown by phosphorylation of its substrates and inhibition of these responses by drugs that prevent mTOR activation. NT-stimulated responses are inhibited by the flavonoid methoxyluteolin (0.1–1 μM). The data provide a link between sortilin and the pathological findings of microglia and inflammation of the brain in ASD. Thus, inhibition of this pathway using methoxyluteolin could provide an effective treatment of ASD.

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mentioning

confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

104

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“…PET imaging revealed microglial activation in autistic subjects compared to control subjects. Significantly higher (R)-[ 11 C]PK11195 levels were observed in the cerebellum, midbrain, pons, fusiform gyri, and anterior cingulate and orbitofrontal cortices from young adult subjects with autistic spectrum disorder compared with control subjects [54].…”

Section: Microglial Activation In Psychiatric Disorders Based On Imagmentioning

confidence: 99%

Microglial Gene Expression Alterations in the Brains of Patients with Psychiatric Disorders

Sakai

Takahashi

et al. 2016

NIB

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Abstract.As recent studies have shown that microglia play a key role in inflammation and immunological challenges as well as have broader roles in synaptic modulation in the brain, studies on psychiatric disorders have increasingly focused on microglia. Microglial abnormalities have consistently been observed in psychiatric postmortem brain studies, including altered microglial activation and changes in the protein and mRNA expression levels of microglial marker molecules, such as major histocompatibility complex, class II, DR (HLA-DR), complement receptor type 3 (CD11b), ionized calcium binding adaptor molecule 1 (IBA-1), macrosialin (CD68) and glucose transporter type 5 (GLUT5). Microglial abnormalities have also been observed in positron emission tomography (PET) studies. Recent advances in omics-based microglial gene expression profiling of psychiatric brains may elucidate microglial involvement in the pathogeneses of psychiatric disorders. In the present paper, we review the current status of research on expression profiling of microglia-relevant molecules in psychiatric postmortem and imaging studies and we discuss future research directions.

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“…Microglias, the first and main line of active immune defense of the CNS, may also release proinflammatory cytokines and free radicals if chronically activated [77]. In autism, microglial activation, along with changes in microglial morphology and their gene expression were evident in numerous brain areas linked to behavior and cognition [78,79]. Taken together, while there is a compelling evidence indicating a pivotal role for the immune system in ASD, future studies are requested to dissect out its exact contribution, delineate its temporal involvements, and advance such findings into medical interventions.…”

Section: Hypertestosteronemia: Pathologic Implications and Therapeutimentioning

confidence: 99%

“…Although notspecific enough as diagnostic markers of ASD, they reflect a serious oxidation condition (OS) that mandates supplementation of antioxidants to patient to block further clinical deteriorations [79,91]. A more reliable and sensitive biomarker of OS that showed high credibility in ASD, has been F2t-Isoprostanes (F2-IsoPs), which can be determined either in blood or in urine, and has been found indicative of impaired cognitive function, development, and disrupted behavior for ASD subjects [92].…”

Section: Metabolomics Studies: Pathobiologic Diagnostic and Therapeumentioning

confidence: 99%

Emerging Clues and Altered Metabolic Findings in Autism: Breakthroughs and Prospects from Omics Studies

Mowafy¹

2016

Autism Open Access

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Autism spectrum disorder (ASD) is a pervasive broad-spectrum disorder that involves multifaceted delays in the development of many basic, social, and communication skills. The etiology of ASD is multifactorial and involves interplay among genetic, neurologic, hormonal, metabolic, immune-inflammatory, and environmental factors; which further complicate both the diagnosis and management in affected individuals. This review delineates the underpinnings of clinical challenges posed by ASD, like clinical heterogeneity of patient presentation, unresolved ASD genomic map and deficient drug therapy. Besides, it addresses the emerging pathogenic, etiologic, and diagnostic clues of diverse origins, encompassing genetic-, neurotransmitter-, androgenic-and immunoinflammatory-anomalies in ASD patients, as availed by advances in Omics technologies (like genomics and proteomics). Moreover, as unravelled by metabolomics studies, metabolic flaws that pertain to amino acids, fatty acids, mitochondrial anomalies, and oxidative-stress are highlighted and further correlated with the extent of clinical picture and malbehaviors coherent with ASD patients. Lastly, future directions are underlined to promote and rationalize ASD research so as to help translate its findings into remedy.

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Microglial Activation in Young Adults With Autism Spectrum Disorder

Cited by 415 publications

References 66 publications

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Microglial Gene Expression Alterations in the Brains of Patients with Psychiatric Disorders

Emerging Clues and Altered Metabolic Findings in Autism: Breakthroughs and Prospects from Omics Studies

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