Expression profiling suggests microglial impairment in human immunodeficiency virus neuropathogenesis

Ginsberg, Stephen D.; Alldred, Melissa J.; Gunnam, Satya M.; Schiroli, Consuelo; Lee, Sang H.; Morgello, Susan; Fischer, Tracy

doi:10.1002/ana.25160

Cited by 43 publications

(33 citation statements)

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“…Validation of select transcripts at ;6 mo old was performed by qPCR and by NanoString nCounter through CA1 subregional analysis and not single population analysis because single population analysis does not generate the RNA sample volume necessary for either qPCR or Nano-String nCounter (51,62,63,(76)(77)(78)(79). Subregional analysis by NanoString nCounter (the codeset is listed in Supplemental Table S6) revealed concurrent expression level changes in glutamate ionotropic receptor AMPA type subunit 4 (Gria4) and synaptophysin and trend-level changes in Ntf5 that matched the custom-designed microarray findings (Fig.…”

Section: Resultsmentioning

confidence: 99%

Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

et al. 2019

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Choline is critical for normative function of 3 major pathways in the brain, including acetylcholine biosynthesis, being a key mediator of epigenetic regulation, and serving as the primary substrate for the phosphatidylethanolamine N‐methyltransferase pathway. Sufficient intake of dietary choline is critical for proper brain function and neurodevelopment. This is especially important for brain development during the perinatal period. Current dietary recommendations for choline intake were undertaken without critical evaluation of maternal choline levels. As such, recommended levels may be insufficient for both mother and fetus. Herein, we examined the impact of perinatal maternal choline supplementation (MCS) in a mouse model of Down syndrome and Alzheimer's disease, the Ts65Dn mouse relative to normal disomic littermates, to examine the effects on gene expression within adult offspring at ∼6 and 11 mo of age. We found MCS produces significant changes in offspring gene expression levels that supersede age‐related and genotypic gene expression changes. Alterations due to MCS impact every gene ontology category queried, including GABAergic neurotransmission, the endosomal‐lysosomal pathway and autophagy, and neurotrophins, highlighting the importance of proper choline intake during the perinatal period, especially when the fetus is known to have a neurodevelopmental disorder such as trisomy.—Alldred, M. J., Chao, H. M., Lee, S. H., Beilin, J., Powers, B. E., Petkova, E., Strupp, B. J., Ginsberg, S. D. Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease. FASEB J. 33, 9871–9884 (2019). http://www.fasebj.org

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Section: Resultsmentioning

confidence: 99%

Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

et al. 2019

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“…As an example, "humanized" bone marrow chimeric mice are susceptible to brain infection by HIV, when the transplanted cells develop into cells with microglia properties within the CNS (Mathews et al, 2019). In addition, as shown by single cell gene expression analysis, chronic microglia infection in the AIDS brain may result in their functional impairment and senescence, which may impair their homeostatic function in chronic brain inflammation (Chen, Partridge, Sell, Torres, & Martin-Garcia, 2017;Ginsberg et al, 2018).…”

Section: Activated Microglia and Macrophages Are Abundant In Active Msmentioning

confidence: 99%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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Numerous recent studies have been performed to elucidate the function of microglia, macrophages, and astrocytes in inflammatory diseases of the central nervous system. Regarding myeloid cells a core pattern of activation has been identified, starting with the activation of resident homeostatic microglia followed by recruitment of blood borne myeloid cells. An initial state of proinflammatory activation is at later stages followed by a shift toward an‐anti‐inflammatory and repair promoting phenotype. Although this core pattern is similar between experimental models and inflammatory conditions in the human brain, there are important differences. Even in the normal human brain a preactivated microglia phenotype is evident, and there are disease specific and lesion stage specific differences in the contribution between resident and recruited myeloid cells and their lesion state specific activation profiles. Reasons for these findings reside in species related differences and in differential exposure to different environmental cues. Most importantly, however, experimental rodent studies on brain inflammation are mainly focused on autoimmune encephalomyelitis, while there is a very broad spectrum of human inflammatory diseases of the central nervous system, triggered and propagated by a variety of different immune mechanisms.

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“…However, the two other cytokines tested: IL-174 6 and IL-10, did not change across any condition (Figure 2-figure supplement 3a-3c). IL-8 175 production was increased in cultured, infected, fetal microglia (Tatro,Soontornniyomkij,176 Letendre, & Achim, 2014), and IL-1b RNA was increased in laser-captured microglia from brain 177 samples of HIV-infected patients (Ginsberg et al, 2018). Infected iMg cultures exposed to EFZ 178 had mitigated, non-significant responses to IL-1b, IL-8, TNFa, and IL-1a ( Figures 2f-2i), suggesting 179 a reduced inflammatory reaction.…”

Section: Img Are Productively Infected With Hiv and Respond To Multipmentioning

confidence: 99%

Neuroinflammation and EIF2 signaling persist in an HiPSC tri-culture model of HIV infection despite antiretroviral treatment

Ryan¹,

Gonzalez²,

Garifallou³

et al. 2019

Preprint

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23 HIV-Associated Neurocognitive Disorders (HAND) affect over half of HIV-infected individuals 24 worldwide, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms 25 underlying HAND remain elusive. We developed a human-induced pluripotent stem cell (HiPSC) 26 based model; whereby, we independently differentiate HiPSCs into neurons, astrocytes, and 27 microglia and systematically combine to generate a tri-culture with or without HIV-infection and 28 ART. scRNAseq analysis on tri-cultures including HIV-infected microglia revealed inflammatory 29 signatures in the microglia and EIF2 signaling in all three cell types. Remarkably, EFZ alone 30 induced a similar response to infection. Treatment with the antiretroviral compound Efavirenz 31 (EFZ) mostly resolved these signatures; However, EFZ increased RhoGDI and CD40 signaling in 32 the HIV-infected microglia. This activation was associated with a persistent increase in TNFa 33 expression. This work establishes a tri-culture that recapitulates key features of HIV infection in 34 the CNS and provides a new model to examine the effects of HIV infection and its treatment with 35 antiretrovirals. 36

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Expression profiling suggests microglial impairment in human immunodeficiency virus neuropathogenesis

Cited by 43 publications

References 50 publications

Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Neuroinflammation and EIF2 signaling persist in an HiPSC tri-culture model of HIV infection despite antiretroviral treatment

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