Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum

Azmitia, Efrain C.; Saccomano, ZT; Alzoobaee, M. F.; Boldrini, Maura; Whitaker‐Azmitia, Patricia M.

doi:10.1007/s10803-015-2672-6

Cited by 52 publications

(53 citation statements)

References 85 publications

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“…Interneuron impairment leading to neuronal hyper‐synchrony is a central theme of Alzheimer's disease, epilepsy, schizophrenia, and autism (Vagnucci Jr. & Li, ). Co‐incidence of angiogenic dysfunction is an additional feature of these neuropathological conditions (Azmitia, Saccomano, Alzoobaee, Boldrini, & Whitaker‐Azmitia, ). Our findings provide limited indirect evidence for causative contribution by angiogenic dysfunction to the observed interneuron imbalance rather than a simple co‐incidence.…”

Section: Discussionmentioning

confidence: 99%

Neural microvascular pericytes contribute to human adult neurogenesis

Farahani

Rezaei-Lotfi

Simonian

et al. 2018

J of Comparative Neurology

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Consistent adult neurogenic activity in humans is observed in specific niches within the central nervous system. However, the notion of an adult neurogenic niche is challenged by accumulating evidence for ectopic neurogenic activity in other cerebral locations. Herein we interface precision of ultrastructural resolution and anatomical simplicity of accessible human dental pulp neurogenic zone to address this conflict. We disclose a basal level of adult neurogenic activity characterized by glial invasion of terminal microvasculature followed by release of individual platelet‐derived growth factor receptor‐β mural pericytes and subsequent reprogramming into NeuN+ local interneurons. Concomitant angiogenesis, a signature of adult neurogenic niches, accelerates the rate of neurogenesis by amplifying release and proliferation of the mural pericyte population by ≈10‐fold. Subsequent in vitro and in vivo experiments confirmed gliogenic and neurogenic capacities of human neural pericytes. Findings foreshadow the bimodal nature of the glio‐vascular assembly where pericytes, under instruction from glial cells, can stabilize the quiescent microvasculature or enrich local neuronal microcircuits upon differentiation.

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Section: Discussionmentioning

confidence: 99%

Neural microvascular pericytes contribute to human adult neurogenesis

Farahani

Rezaei-Lotfi

Simonian

et al. 2018

J of Comparative Neurology

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“…Stereological quantification would be required to confirm these findings. The presence of nestin-immunoreactive pericytes and CD-34-immunoreactive endothelial cells indicates that vascular remodeling persists in the superior temporal cortex, fusiform cortex, midbrain and cerebellum in ASD beyond childhood when they usually decline in controls [15]. The pathology of microglia in ASD has also been assessed in a few patient studies.…”

Section: Neuropathology Of Asd: Recent Findings From Human Studiesmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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“…Overexpressing VEGF-A 165 also increases blood-brain barrier (BBB) permeability [62]. Consistent with the consequences of VEGF-A overexpression observed in rodents, ASD patients have increased neurogenesis in the frontal cortex [63,64], persistent angiogenesis [65], increased white matter metabolic rates in the frontal lobes [66], and apparent altered BBB permeability [67,68].…”

Section: Resultsmentioning

confidence: 86%

Vascular endothelial growth factor (VEGF) expression and neuroinflammation is increased in the frontopolar cortex of individuals with autism spectrum disorder

Gnanasekaran

et al. 2019

Preprint

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14Autism spectrum disorder (ASD) etiology is a complex mixture of genetic and 15 environmental factors, the relative contributions of which varies across patients. Despite 16 complex etiology, researchers observe consistent neurodevelopmental features in ASD 17 patients, notably atypical forebrain cortical development. Growth factors, cytokines, and 18 chemokines are important mediators of forebrain cortical development, but have not been 19 thoroughly examined in brain tissues from individuals with autism. Here, we performed an 20 integrative analysis of RNA and protein expression using frontopolar cortex tissues dissected 21 from individuals with ASD and controls, hypothesizing that ASD patients will exhibit aberrant 22 expression of growth factors, cytokines, and chemokines critical for neurodevelopment. We 23 performed group-wise comparisons of RNA expression via RNA-Seq and growth factor, 24cytokine, and chemokine expression via multiplex enzyme-linked immunosorbent assay 25 (ELISA). We also analyzed single cell sequencing data from the frontopolar cortex of typically 26 developed individuals to identify cell types that express the growth factors we found differentially 27 expressed in ASD. Our RNA-Seq analysis revealed 11 differentially expressed genes in ASD 28 versus control brains, the most significant of which encodes for vascular endothelial growth 29 factor (VEGF-A). Both RNA and protein levels of VEGF-A were upregulated in ASD brains. Our 30 single cell analysis revealed that VEGF is expressed primarily by non-neuronal cells. We also 31 found that the differentially expressed genes from our RNA-Seq analysis are enriched in 32 microglia. The increased VEGF-A expression we observed in ASD, coupled with the enrichment 33 of differentially expressed genes in microglia, begs the question of the role VEGF-A is playing in 34 ASD. Microglia activation, as indicated by our RNA-Seq results, and the VEGF-A isoform 35 expression we see in the ASD cortex, leads us to conclude that VEGF-A is playing a pro-36 inflammatory role, perhaps with unwanted long-term consequences for neurodevelopment.

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Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum

Cited by 52 publications

References 85 publications

Neural microvascular pericytes contribute to human adult neurogenesis

Neural microvascular pericytes contribute to human adult neurogenesis

Autism spectrum disorder: neuropathology and animal models

Vascular endothelial growth factor (VEGF) expression and neuroinflammation is increased in the frontopolar cortex of individuals with autism spectrum disorder

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