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  1. Article ; Online: Insight into the role of phosphatidylserine in complement-mediated synapse loss in Alzheimer's disease.

    Sokolova, Dimitra / Childs, Thomas / Hong, Soyon

    Faculty reviews

    2021  Volume 10, Page(s) 19

    Abstract: The innate immune system plays an integral role in the brain. Synaptic pruning, a fundamental process in developmental circuit refinement, is partially mediated by neuroimmune signalling at the synapse. In particular, microglia, the major tissue-resident ...

    Abstract The innate immune system plays an integral role in the brain. Synaptic pruning, a fundamental process in developmental circuit refinement, is partially mediated by neuroimmune signalling at the synapse. In particular, microglia, the major tissue-resident macrophages of the brain, and the classical complement cascade, an innate immune pathway that aids in the clearance of unwanted material, have been implicated in mediating synapse elimination. Emerging data suggest that improper signalling of the innate immune pathway at the synapse leads to pathological synapse loss in age-related neurodegenerative diseases, including Alzheimer's disease. Now the key questions are whether synapses are targeted by complement and, if so, which synapses are vulnerable to elimination. Here, we review recent work implicating C1q, the initiator of the classical complement cascade, and surrounding glia as mediators of synapse loss. We examine how synapses could undergo apoptosis-like pathways in the Alzheimer brain, which may lead to the externalisation of phosphatidylserine on synapses. Finally, we discuss potential roles for microglia and astrocytes in this 'synaptic apoptosis'. Critical insight into neuroimmune regulatory pathways on synapses will be key to developing effective targets against pathological synapse loss in dementia.
    Language English
    Publishing date 2021-02-24
    Publishing country England
    Document type Journal Article ; Review
    ISSN 2732-432X
    ISSN (online) 2732-432X
    DOI 10.12703/r/10-19
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models.

    Rueda-Carrasco, Javier / Sokolova, Dimitra / Lee, Sang-Eun / Childs, Thomas / Jurčáková, Natália / Crowley, Gerard / De Schepper, Sebastiaan / Ge, Judy Z / Lachica, Joanne I / Toomey, Christina E / Freeman, Oliver J / Hardy, John / Barnes, Samuel J / Lashley, Tammaryn / Stevens, Beth / Chang, Sunghoe / Hong, Soyon

    The EMBO journal

    2023  Volume 42, Issue 19, Page(s) e113246

    Abstract: Neuronal hyperactivity is a key feature of early stages of Alzheimer's disease (AD). Genetic studies in AD support that microglia act as potential cellular drivers of disease risk, but the molecular determinants of microglia-synapse engulfment associated ...

    Abstract Neuronal hyperactivity is a key feature of early stages of Alzheimer's disease (AD). Genetic studies in AD support that microglia act as potential cellular drivers of disease risk, but the molecular determinants of microglia-synapse engulfment associated with neuronal hyperactivity in AD are unclear. Here, using super-resolution microscopy, 3D-live imaging of co-cultures, and in vivo imaging of lipids in genetic models, we found that spines become hyperactive upon Aβ oligomer stimulation and externalize phosphatidylserine (ePtdSer), a canonical "eat-me" signal. These apoptotic-like spines are targeted by microglia for engulfment via TREM2 leading to amelioration of Aβ oligomer-induced synaptic hyperactivity. We also show the in vivo relevance of ePtdSer-TREM2 signaling in microglia-synapse engulfment in the hAPP NL-F knock-in mouse model of AD. Higher levels of apoptotic-like synapses in mice as well as humans that carry TREM2 loss-of-function variants were also observed. Our work supports that microglia remove hyperactive ePtdSer
    MeSH term(s) Humans ; Mice ; Animals ; Alzheimer Disease/genetics ; Microglia ; Synapses ; Disease Models, Animal ; Amyloid beta-Peptides/genetics ; Membrane Glycoproteins/genetics ; Receptors, Immunologic/genetics
    Chemical Substances Amyloid beta-Peptides ; TREM2 protein, human ; Membrane Glycoproteins ; Receptors, Immunologic
    Language English
    Publishing date 2023-08-14
    Publishing country England
    Document type Journal Article
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.15252/embj.2022113246
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1808: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 100: Show issues

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  3. Article ; Online: Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease.

    De Schepper, Sebastiaan / Ge, Judy Z / Crowley, Gerard / Ferreira, Laís S S / Garceau, Dylan / Toomey, Christina E / Sokolova, Dimitra / Rueda-Carrasco, Javier / Shin, Sun-Hye / Kim, Jung-Seok / Childs, Thomas / Lashley, Tammaryn / Burden, Jemima J / Sasner, Michael / Sala Frigerio, Carlo / Jung, Steffen / Hong, Soyon

    Nature neuroscience

    2023  Volume 26, Issue 3, Page(s) 406–415

    Abstract: Alzheimer's disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD is unclear. Here we ... ...

    Abstract Alzheimer's disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD is unclear. Here we report that secreted phosphoprotein 1 (SPP1/osteopontin) is upregulated predominantly by perivascular macrophages and, to a lesser extent, by perivascular fibroblasts. Perivascular SPP1 is required for microglia to engulf synapses and upregulate phagocytic markers including C1qa, Grn and Ctsb in presence of amyloid-β oligomers. Absence of Spp1 expression in AD mouse models results in prevention of synaptic loss. Furthermore, single-cell RNA sequencing and putative cell-cell interaction analyses reveal that perivascular SPP1 induces microglial phagocytic states in the hippocampus of a mouse model of AD. Altogether, we suggest a functional role for SPP1 in perivascular cells-to-microglia crosstalk, whereby SPP1 modulates microglia-mediated synaptic engulfment in mouse models of AD.
    MeSH term(s) Mice ; Animals ; Alzheimer Disease/metabolism ; Microglia/metabolism ; Osteopontin/metabolism ; Phagocytes/metabolism ; Macrophages/metabolism ; Phagocytosis ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism
    Chemical Substances Osteopontin (106441-73-0) ; Amyloid beta-Peptides ; Spp1 protein, mouse
    Language English
    Publishing date 2023-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1420596-8
    ISSN 1546-1726 ; 1097-6256
    ISSN (online) 1546-1726
    ISSN 1097-6256
    DOI 10.1038/s41593-023-01257-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4891: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 67: Show issues

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  4. Article ; Online: A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene.

    Magusali, Naciye / Graham, Andrew C / Piers, Thomas M / Panichnantakul, Pantila / Yaman, Umran / Shoai, Maryam / Reynolds, Regina H / Botia, Juan A / Brookes, Keeley J / Guetta-Baranes, Tamar / Bellou, Eftychia / Bayram, Sevinc / Sokolova, Dimitra / Ryten, Mina / Sala Frigerio, Carlo / Escott-Price, Valentina / Morgan, Kevin / Pocock, Jennifer M / Hardy, John /
    Salih, Dervis A

    Brain : a journal of neurology

    2021  Volume 144, Issue 12, Page(s) 3727–3741

    Abstract: Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer's disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping ... ...

    Abstract Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer's disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer's disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer's disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer's disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer's disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells. Collectively, our data support a link between genetic risk for Alzheimer's disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer's disease and COVID-19, and development of biomarkers to track disease progression.
    MeSH term(s) 2',5'-Oligoadenylate Synthetase/genetics ; Adolescent ; Aged ; Aged, 80 and over ; Alzheimer Disease/diagnosis ; Alzheimer Disease/epidemiology ; Alzheimer Disease/genetics ; COVID-19/diagnosis ; COVID-19/epidemiology ; COVID-19/genetics ; Cells, Cultured ; Female ; Gene Regulatory Networks/genetics ; Genetic Linkage/genetics ; Genetic Predisposition to Disease/epidemiology ; Genetic Predisposition to Disease/genetics ; Humans ; Induced Pluripotent Stem Cells/physiology ; Male ; Middle Aged ; Patient Acuity ; Polymorphism, Single Nucleotide/genetics ; Young Adult
    Chemical Substances OAS1 protein, human (EC 2.7.7.-) ; 2',5'-Oligoadenylate Synthetase (EC 2.7.7.84)
    Language English
    Publishing date 2021-10-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awab337
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Genetic variability associated with OAS1 expression in myeloid cells increases the risk of Alzheimer's disease and severe COVID-19 outcomes

    Magusali, Naciye / Graham, Andrew C / Piers, Thomas M / Panichnantakul, Pantila / Yaman, Umran / Shoai, Maryam / Reynolds, Regina H / Botia, Juan A. / Brookes, Keeley J / Guetta-Baranes, Tamar / Bellou, Eftychia / Bayram, Sevinc / Sokolova, Dimitra / Ryten, Mina / Sala Frigerio, Carlo / Escott-Price, Valentina / Morgan, Kevin / Pocock, Jennifer M / Hardy, John /
    Salih, Dervis A

    bioRxiv

    Abstract: Genome-wide association studies of late-onset Alzheimer9s disease (AD) have highlighted the importance of variants associated with genes expressed by the innate immune system in determining risk for AD. Recently, we and others have shown that genes ... ...

    Abstract Genome-wide association studies of late-onset Alzheimer9s disease (AD) have highlighted the importance of variants associated with genes expressed by the innate immune system in determining risk for AD. Recently, we and others have shown that genes associated with variants that confer risk for AD are significantly enriched in transcriptional networks expressed by amyloid-responsive microglia. This allowed us to predict new risk genes for AD, including the interferon-responsive oligoadenylate synthetase 1 (OAS1). However, the function of OAS1 within microglia and its genetic pathway are not known. Using genotyping from 1,313 individuals with sporadic AD and 1,234 control individuals, we confirm that the OAS1 variant, rs1131454, is associated with increased risk for AD and decreased OAS1 expression. Moreover, we note that the same locus was recently associated with critical illness in response to COVID-19, linking variants that are associated with AD and a severe response to COVID-19. By analysing single-cell RNA-sequencing (scRNA-seq) data of isolated microglia from APPNL-G-F knock-in and wild-type C57BL/6J mice, we identify a transcriptional network that is significantly upregulated with age and amyloid deposition, and contains the mouse orthologue Oas1a, providing evidence that Oas1a plays an age-dependent function in the innate immune system. We identify a similar interferon-related transcriptional network containing OAS1 by analysing scRNA-seq data from human microglia isolated from individuals with AD. Finally, using human iPSC-derived microglial cells (h-iPSC-Mg), we see that OAS1 is required to limit the pro-inflammatory response of microglia. When stimulated with interferon-gamma (IFN-γ), we note that cells with lower OAS1 expression show an exaggerated pro-inflammatory response, with increased expression and secretion of TNF-α. Collectively, our data support a link between genetic risk for AD and susceptibility to critical illness with COVID-19 centred on OAS1 and interferon signalling, a finding with potential implications for future treatments of both AD and COVID-19, and the development of biomarkers to track disease progression.
    Keywords covid19
    Language English
    Publishing date 2021-03-18
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.03.16.435702
    Database COVID19

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