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  1. Article: Dissecting the Ability of Siglecs To Antagonize Fcγ Receptors.

    McCord, Kelli A / Wang, Chao / Anhalt, Mirjam / Poon, Wayne W / Gavin, Amanda L / Wu, Peng / Macauley, Matthew S

    ACS central science

    2024  Volume 10, Issue 2, Page(s) 315–330

    Abstract: Fcγ receptors (FcγRs) play key roles in the effector function of IgG, but their inappropriate activation plays a role in several disease etiologies. Therefore, it is critical to better understand how FcγRs are regulated. Numerous studies suggest that ... ...

    Abstract Fcγ receptors (FcγRs) play key roles in the effector function of IgG, but their inappropriate activation plays a role in several disease etiologies. Therefore, it is critical to better understand how FcγRs are regulated. Numerous studies suggest that sialic acid-binding immunoglobulin-type lectins (Siglecs), a family of immunomodulatory receptors, modulate FcγR activity; however, it is unclear of the circumstances in which Siglecs can antagonize FcγRs and which Siglecs have this ability. Using liposomes displaying selective ligands to coengage FcγRs with a specific Siglec, we explore the ability of Siglec-3, Siglec-5, Siglec-7, and Siglec-9 to antagonize signaling downstream of FcγRs. We demonstrate that Siglec-3 and Siglec-9 can fully inhibit FcγR activation in U937 cells when coengaged with FcγRs. Cells expressing Siglec mutants reveal differential roles for the immunomodulatory tyrosine-based inhibitory motif (ITIM) and immunomodulatory tyrosine-based switch motif (ITSM) in this inhibition. Imaging flow cytometry enabled visualization of SHP-1 recruitment to Siglec-3 in an ITIM-dependent manner, while SHP-2 recruitment is more ITSM-dependent. Conversely, both cytosolic motifs of Siglec-9 contribute to SHP-1/2 recruitment. Siglec-7 poorly antagonizes FcγR activation for two reasons: masking by cis ligands and differences in its ITIM and ITSM. A chimera of the Siglec-3 extracellular domains and Siglec-5 cytosolic tail strongly inhibits FcγR when coengaged, providing evidence that Siglec-5 is more like Siglec-3 and Siglec-9 in its ability to antagonize FcγRs. Additionally, Siglec-3 and Siglec-9 inhibited FcγRs when coengaged by cells displaying ligands for both the Siglec and FcγRs. These results suggest a role for Siglecs in mediating FcγR inhibition in the context of an immunological synapse, which has important relevance to the effectiveness of immunotherapies.
    Language English
    Publishing date 2024-01-17
    Publishing country United States
    Document type Journal Article
    ISSN 2374-7943
    ISSN 2374-7943
    DOI 10.1021/acscentsci.3c00969
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  2. Article ; Online: Human neural cell type-specific extracellular vesicle proteome defines disease-related molecules associated with activated astrocytes in Alzheimer's disease brain.

    You, Yang / Muraoka, Satoshi / Jedrychowski, Mark P / Hu, Jianqiao / McQuade, Amanda K / Young-Pearse, Tracy / Aslebagh, Roshanak / Shaffer, Scott A / Gygi, Steven P / Blurton-Jones, Mathew / Poon, Wayne W / Ikezu, Tsuneya

    Journal of extracellular vesicles

    2021  Volume 11, Issue 1, Page(s) e12183

    Abstract: In neurodegenerative diseases, extracellular vesicles (EVs) transfer pathogenic molecules and are consequently involved in disease progression. We have investigated the proteomic profiles of EVs that were isolated from four different human-induced ... ...

    Abstract In neurodegenerative diseases, extracellular vesicles (EVs) transfer pathogenic molecules and are consequently involved in disease progression. We have investigated the proteomic profiles of EVs that were isolated from four different human-induced pluripotent stem cell-derived neural cell types (excitatory neurons, astrocytes, microglia-like cells, and oligodendrocyte-like cells). Novel cell type-specific EV protein markers were then identified for the excitatory neurons (ATP1A3, NCAM1), astrocytes (LRP1, ITGA6), microglia-like cells (ITGAM, LCP1), and oligodendrocyte-like cells (LAMP2, FTH1), as well as 16 pan-EV marker candidates, including integrins and annexins. To further demonstrate how cell-type-specific EVs may be involved in Alzheimer's disease (AD), we performed protein co-expression network analysis and conducted cell type assessments for the proteomes of brain-derived EVs from the control, mild cognitive impairment, and AD cases. A protein module enriched in astrocyte-specific EV markers was most significantly associated with the AD pathology and cognitive impairment, suggesting an important role in AD progression. The hub protein from this module, integrin-β1 (ITGB1), was found to be significantly elevated in astrocyte-specific EVs enriched from the total brain-derived AD EVs and associated with the brain β-amyloid and tau load in independent cohorts. Thus, our study provides a featured framework and rich resource for the future analyses of EV functions in neurodegenerative diseases in a cell type-specific manner.
    MeSH term(s) Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Astrocytes/metabolism ; Biomarkers/metabolism ; Brain/cytology ; Brain/metabolism ; Cognitive Dysfunction/metabolism ; Cognitive Dysfunction/pathology ; Extracellular Vesicles/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Integrin beta1/metabolism ; Proteome/metabolism ; tau Proteins/metabolism
    Chemical Substances Amyloid beta-Peptides ; Biomarkers ; Integrin beta1 ; Itgb1 protein, human ; Proteome ; tau Proteins
    Language English
    Publishing date 2021-12-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2683797-3
    ISSN 2001-3078 ; 2001-3078
    ISSN (online) 2001-3078
    ISSN 2001-3078
    DOI 10.1002/jev2.12183
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  3. Article ; Online: Tau Spread, Apolipoprotein E, Inflammation, and More: Rapidly Evolving Basic Science in Alzheimer Disease.

    Gonzalez, Bianca / Abud, Edsel M / Abud, Abigail M / Poon, Wayne W / Gylys, Karen H

    Neurologic clinics

    2017  Volume 35, Issue 2, Page(s) 175–190

    Abstract: To date, Alzheimer disease drug candidates have produced negative results in human trials, and progress in moving new targets out of the laboratory and into trials has been slow. However, based on 3 decades of previous work, there is reason to hope that ... ...

    Abstract To date, Alzheimer disease drug candidates have produced negative results in human trials, and progress in moving new targets out of the laboratory and into trials has been slow. However, based on 3 decades of previous work, there is reason to hope that amyloid-based and other novel therapies will move at a faster pace toward successful clinical trials. This article highlights selected preclinical research topics that are rapidly advancing in the laboratory.
    MeSH term(s) Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Apolipoproteins E/genetics ; Apolipoproteins E/metabolism ; Brain/metabolism ; Brain/pathology ; Cholesterol/metabolism ; Humans ; Inflammation/complications ; tau Proteins/metabolism
    Chemical Substances Apolipoproteins E ; tau Proteins ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2017-05
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1013148-6
    ISSN 1557-9875 ; 0733-8619
    ISSN (online) 1557-9875
    ISSN 0733-8619
    DOI 10.1016/j.ncl.2017.01.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Se 854: Show issues Location:
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  4. Article ; Online: Caspase-cleaved glial fibrillary acidic protein within cerebellar white matter of the Alzheimer's disease brain.

    Rohn, Troy T / Catlin, Lindsey W / Poon, Wayne W

    International journal of clinical and experimental pathology

    2012  Volume 6, Issue 1, Page(s) 41–48

    Abstract: Although the cerebellum is generally thought of as an area spared of Alzheimer's disease (AD) pathology, recent evidence suggests that balance and mobility dysfunction may be magnified in affected individuals. In the present study, we sought to determine ...

    Abstract Although the cerebellum is generally thought of as an area spared of Alzheimer's disease (AD) pathology, recent evidence suggests that balance and mobility dysfunction may be magnified in affected individuals. In the present study, we sought to determine the degree of pathological changes within the cerebellum utilizing an antibody that specifically detects caspase-cleaved GFAP within degenerating astrocytes. Compared to control subjects, application of this antibody, termed the GFAP caspase-cleavage product (GFAPccp) antibody, revealed widespread labeling in cerebellar white matter with little staining observed in grey matter. Staining was observed within damaged astrocytes, was often localized near blood vessels and co-localized with other markers of apoptosis including TUNEL and caspase-cleaved tau. Of interest was the association of beta-amyloid deposition in white matter together with GFAPccp in cerebellar AD sections. In contrast, utilizing the tangle marker, PHF-1, neuritic pathology was completely absent in AD cerebellar sections. It is suggested that the observed pathological changes found in the white matter of the cerebellum may contribute to the declined motor performance in AD.
    MeSH term(s) Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Apoptosis/physiology ; Caspases/metabolism ; Cerebellum/metabolism ; Cerebellum/pathology ; Glial Fibrillary Acidic Protein/analysis ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Microscopy, Fluorescence ; Nerve Fibers, Myelinated/metabolism ; Nerve Fibers, Myelinated/pathology
    Chemical Substances Glial Fibrillary Acidic Protein ; Caspases (EC 3.4.22.-)
    Language English
    Publishing date 2012-11-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2418306-4
    ISSN 1936-2625 ; 1936-2625
    ISSN (online) 1936-2625
    ISSN 1936-2625
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  5. Article: Cholesterol and matrisome pathways dysregulated in astrocytes and microglia

    TCW, Julia / Qian, Lu / Pipalia, Nina H. / Chao, Michael J. / Liang, Shuang A. / Shi, Yang / Jain, Bharat R. / Bertelsen, Sarah E. / Kapoor, Manav / Marcora, Edoardo / Sikora, Elizabeth / Andrews, Elizabeth J. / Martini, Alessandra C. / Karch, Celeste M. / Head, Elizabeth / Holtzman, David M. / Zhang, Bin / Wang, Minghui / Maxfield, Frederick R. /
    Poon, Wayne W. / Goate, Alison M.

    Cell. 2022 June 23, v. 185, no. 13

    2022  

    Abstract: The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and ... ...

    Abstract The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.
    Keywords alleles ; apolipoprotein E ; astrocytes ; biosynthesis ; brain ; chemotaxis ; cholesterol ; coculture ; haplotypes ; humans ; risk factors ; transcriptomics
    Language English
    Dates of publication 2022-0623
    Size p. 2213-2233.e25.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2022.05.017
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  6. Article ; Online: Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes.

    Novikova, Gloriia / Kapoor, Manav / Tcw, Julia / Abud, Edsel M / Efthymiou, Anastasia G / Chen, Steven X / Cheng, Haoxiang / Fullard, John F / Bendl, Jaroslav / Liu, Yiyuan / Roussos, Panos / Björkegren, Johan Lm / Liu, Yunlong / Poon, Wayne W / Hao, Ke / Marcora, Edoardo / Goate, Alison M

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 1610

    Abstract: Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD ... ...

    Abstract Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.
    MeSH term(s) Alleles ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Gene Expression Regulation ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Genomics ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Macrophages ; Microglia/metabolism ; Myeloid Cells ; Regulatory Sequences, Nucleic Acid/genetics ; Transcriptome
    Language English
    Publishing date 2021-03-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-21823-y
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  7. Article ; Online: Exosomal tau with seeding activity is released from Alzheimer's disease synapses, and seeding potential is associated with amyloid beta.

    Miyoshi, Emily / Bilousova, Tina / Melnik, Mikhail / Fakhrutdinov, Danyl / Poon, Wayne W / Vinters, Harry V / Miller, Carol A / Corrada, Maria / Kawas, Claudia / Bohannan, Ryan / Caraway, Chad / Elias, Chris / Maina, Katherine N / Campagna, Jesus J / John, Varghese / Gylys, Karen Hoppens

    Laboratory investigation; a journal of technical methods and pathology

    2021  Volume 101, Issue 12, Page(s) 1605–1617

    Abstract: Synaptic transfer of tau has long been hypothesized from the human pathology pattern and has been demonstrated in vitro and in vivo, but the precise mechanisms remain unclear. Extracellular vesicles such as exosomes have been suggested as a mechanism, ... ...

    Abstract Synaptic transfer of tau has long been hypothesized from the human pathology pattern and has been demonstrated in vitro and in vivo, but the precise mechanisms remain unclear. Extracellular vesicles such as exosomes have been suggested as a mechanism, but not all tau is exosomal. The present experiments use a novel flow cytometry assay to quantify depolarization of synaptosomes by KCl after loading with FM2-10, which induces a fluorescence reduction associated with synaptic vesicle release; the degree of reduction in cryopreserved human samples equaled that seen in fresh mouse synaptosomes. Depolarization induced the release of vesicles in the size range of exosomes, along with tetraspanin markers of extracellular vesicles. A number of tau peptides were released, including tau oligomers; released tau was primarily unphosphorylated and C-terminal truncated, with Aβ release just above background. When exosomes were immunopurified from release supernatants, a prominent tau band showed a dark smeared appearance of SDS-stable oligomers along with the exosomal marker syntenin-1, and these exosomes induced aggregation in the HEK tau biosensor assay. However, the flow-through did not seed aggregation. Size exclusion chromatography of purified released exosomes shows faint signals from tau in the same fractions that show a CD63 band, an exosomal size signal, and seeding activity. Crude synaptosomes from control, tauopathy, and AD cases demonstrated lower seeding in tauopathy compared to AD that is correlated with the measured Aβ42 level. These results show that AD synapses release exosomal tau that is C-terminal-truncated, oligomeric, and with seeding activity that is enhanced by Aβ. Taken together with previous findings, these results are consistent with a direct prion-like heterotypic seeding of tau by Aβ within synaptic terminals, with subsequent loading of aggregated tau onto exosomes that are released and competent for tau seeding activity.
    MeSH term(s) Aged ; Aged, 80 and over ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Animals ; Cerebral Cortex/metabolism ; Cerebral Cortex/pathology ; Extracellular Vesicles/metabolism ; Female ; Humans ; Male ; Mice ; Middle Aged ; Protein Aggregation, Pathological ; Synapses/metabolism ; Synaptosomes/metabolism ; tau Proteins/metabolism
    Chemical Substances Amyloid beta-Peptides ; tau Proteins
    Language English
    Publishing date 2021-08-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80178-1
    ISSN 1530-0307 ; 0023-6837
    ISSN (online) 1530-0307
    ISSN 0023-6837
    DOI 10.1038/s41374-021-00644-z
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    In stock of ZB MED Cologne/Königswinter

    Ud II Zs.164: Show issues Location:
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  8. Article ; Online: Caspase-Cleaved Tau Co-Localizes with Early Tangle Markers in the Human Vascular Dementia Brain.

    Day, Ryan J / Mason, Maria J / Thomas, Chloe / Poon, Wayne W / Rohn, Troy T

    PloS one

    2015  Volume 10, Issue 7, Page(s) e0132637

    Abstract: Vascular dementia (VaD) is the second most common form of dementia in the United States and is characterized as a cerebral vessel vascular disease that leads to ischemic episodes. Whereas the relationship between caspase-cleaved tau and neurofibrillary ... ...

    Abstract Vascular dementia (VaD) is the second most common form of dementia in the United States and is characterized as a cerebral vessel vascular disease that leads to ischemic episodes. Whereas the relationship between caspase-cleaved tau and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) has been previously described, whether caspase activation and cleavage of tau occurs in VaD is presently unknown. To investigate a potential role for caspase-cleaved tau in VaD, we analyzed seven confirmed cases of VaD by immunohistochemistry utilizing a well-characterized antibody that specifically detects caspase-cleaved tau truncated at Asp421. Application of this antibody (TauC3) revealed consistent labeling within NFTs, dystrophic neurites within plaque-rich regions and corpora amylacea (CA) in the human VaD brain. Labeling of CA by the TauC3 antibody was widespread throughout the hippocampus proper, was significantly higher compared to age matched controls, and co-localized with ubiquitin. Staining of the TauC3 antibody co-localized with MC-1, AT8, and PHF-1 within NFTs. Quantitative analysis indicated that roughly 90% of PHF-1-labeled NFTs contained caspase-cleaved tau. In addition, we documented the presence of active caspase-3 within plaques, blood vessels and pretangle neurons that co-localized with TauC3. Collectively, these data support a role for the activation of caspase-3 and proteolytic cleavage of TauC3 in VaD providing further support for the involvement of this family of proteases in NFT pathology.
    MeSH term(s) Aged ; Aged, 80 and over ; Biomarkers/metabolism ; Brain/enzymology ; Brain/metabolism ; Brain/pathology ; Caspase 3/metabolism ; Dementia, Vascular/metabolism ; Dementia, Vascular/pathology ; Demography ; Enzyme Activation ; Female ; Hippocampus/metabolism ; Humans ; Male ; Neurofibrillary Tangles/metabolism ; Plaque, Amyloid/metabolism ; Plaque, Amyloid/pathology ; Protein Transport ; tau Proteins/metabolism
    Chemical Substances Biomarkers ; tau Proteins ; Caspase 3 (EC 3.4.22.-)
    Language English
    Publishing date 2015-07-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0132637
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  9. Article ; Online: Cholesterol and matrisome pathways dysregulated in astrocytes and microglia.

    Tcw, Julia / Qian, Lu / Pipalia, Nina H / Chao, Michael J / Liang, Shuang A / Shi, Yang / Jain, Bharat R / Bertelsen, Sarah E / Kapoor, Manav / Marcora, Edoardo / Sikora, Elizabeth / Andrews, Elizabeth J / Martini, Alessandra C / Karch, Celeste M / Head, Elizabeth / Holtzman, David M / Zhang, Bin / Wang, Minghui / Maxfield, Frederick R /
    Poon, Wayne W / Goate, Alison M

    Cell

    2022  Volume 185, Issue 13, Page(s) 2213–2233.e25

    Abstract: The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and ... ...

    Abstract The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.
    MeSH term(s) Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Animals ; Apolipoprotein E3/genetics ; Apolipoprotein E3/metabolism ; Apolipoprotein E4/genetics ; Apolipoprotein E4/metabolism ; Apolipoproteins E/genetics ; Apolipoproteins E/metabolism ; Astrocytes/metabolism ; Cholesterol/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Mice ; Microglia/metabolism
    Chemical Substances Apolipoprotein E3 ; Apolipoprotein E4 ; Apolipoproteins E ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2022-06-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2022.05.017
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  10. Article ; Online: Single-nuclei transcriptome analysis of Huntington disease iPSC and mouse astrocytes implicates maturation and functional deficits.

    Reyes-Ortiz, Andrea M / Abud, Edsel M / Burns, Mara S / Wu, Jie / Hernandez, Sarah J / McClure, Nicolette / Wang, Keona Q / Schulz, Corey J / Miramontes, Ricardo / Lau, Alice / Michael, Neethu / Miyoshi, Emily / Van Vactor, David / Reidling, John C / Blurton-Jones, Mathew / Swarup, Vivek / Poon, Wayne W / Lim, Ryan G / Thompson, Leslie M

    iScience

    2022  Volume 26, Issue 1, Page(s) 105732

    Abstract: Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene that alters cellular homeostasis, particularly in the striatum and cortex. Astrocyte signaling that establishes and maintains neuronal functions ...

    Abstract Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene that alters cellular homeostasis, particularly in the striatum and cortex. Astrocyte signaling that establishes and maintains neuronal functions are often altered under pathological conditions. We performed single-nuclei RNA-sequencing on human HD patient-induced pluripotent stem cell (iPSC)-derived astrocytes and on striatal and cortical tissue from R6/2 HD mice to investigate high-resolution HD astrocyte cell state transitions. We observed altered maturation and glutamate signaling in HD human and mouse astrocytes. Human HD astrocytes also showed upregulated actin-mediated signaling, suggesting that some states may be cell-autonomous and human specific. In both species, astrogliogenesis transcription factors may drive HD astrocyte maturation deficits, which are supported by rescued climbing deficits in HD drosophila with NFIA knockdown. Thus, dysregulated HD astrocyte states may induce dysfunctional astrocytic properties, in part due to maturation deficits influenced by astrogliogenesis transcription factor dysregulation.
    Language English
    Publishing date 2022-12-06
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2022.105732
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