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Article: Network analysis reveals strain-dependent response to misfolded tau aggregates.

Acri, Dominic J / You, Yanwen / Tate, Mason D / McCord, Brianne / Sharify, A Daniel / John, Sutha / Karahan, Hande / Kim, Byungwook / Dabin, Luke C / Philtjens, Stéphanie / Wijeratne, H R Sagara / McCray, Tyler J / Smith, Daniel C / Bissel, Stephanie J / Lamb, Bruce T / Lasagna-Reeves, Cristian A / Kim, Jungsu

bioRxiv : the preprint server for biology

2023

Abstract: Mouse genetic backgrounds have been shown to modulate amyloid accumulation and propagation of tau aggregates. Previous research into these effects has highlighted the importance of studying the impact of genetic heterogeneity on modeling Alzheimer's ... ...

Abstract	Mouse genetic backgrounds have been shown to modulate amyloid accumulation and propagation of tau aggregates. Previous research into these effects has highlighted the importance of studying the impact of genetic heterogeneity on modeling Alzheimer's disease. However, it is unknown what mechanisms underly these effects of genetic background on modeling Alzheimer's disease, specifically tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing Summary: Seeding of tau predates the phosphorylation and spreading of tau aggregates. Acri and colleagues report transcriptomic responses to tau and elevated tau seeds in wild-derived mice. This paper creates a rich resource by combining genetics, tau biosensor assays, and transcriptomics.
Language	English
Publishing date	2023-01-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.28.526029
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Article ; Online: Network analysis identifies strain-dependent response to tau and tau seeding-associated genes.

Acri, Dominic J / You, Yanwen / Tate, Mason D / Karahan, Hande / Martinez, Pablo / McCord, Brianne / Sharify, A Daniel / John, Sutha / Kim, Byungwook / Dabin, Luke C / Philtjens, Stéphanie / Wijeratne, H R Sagara / McCray, Tyler J / Smith, Daniel C / Bissel, Stephanie J / Lamb, Bruce T / Lasagna-Reeves, Cristian A / Kim, Jungsu

The Journal of experimental medicine

2023 Volume 220, Issue 11

Abstract: Previous research demonstrated that genetic heterogeneity is a critical factor in modeling amyloid accumulation and other Alzheimer's disease phenotypes. However, it is unknown what mechanisms underlie these effects of genetic background on modeling tau ... ...

Abstract	Previous research demonstrated that genetic heterogeneity is a critical factor in modeling amyloid accumulation and other Alzheimer's disease phenotypes. However, it is unknown what mechanisms underlie these effects of genetic background on modeling tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT. To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n = 64) and determined core transcriptional signature conserved in all genetic backgrounds and signature unique to wild-derived backgrounds. By measuring tau seeding activity using the cortex, we identified 19 key genes associated with tau seeding and amyloid response. Interestingly, microglial pathways were strongly associated with tau seeding activity in CAST/EiJ and PWK/PhJ backgrounds. Collectively, our study demonstrates that mouse genetic context affects tau-mediated alteration of transcriptome and tau seeding. The gene modules associated with tau seeding provide an important resource to better model tauopathy.
MeSH term(s)	Animals ; Mice ; Mice, Inbred C57BL ; Alzheimer Disease/genetics ; Tauopathies/genetics ; Brain ; Gene Regulatory Networks
Language	English
Publishing date	2023-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20230180
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Article ; Online: Role of CHI3L1 in neuroinflammation.

Wiley, Clayton A / Bissel, Stephanie J / Murdoch, Geoffrey H

Clinical immunology (Orlando, Fla.)

2015 Volume 161, Issue 2, Page(s) 354

MeSH term(s)	Animals ; Encephalomyelitis, Autoimmune, Experimental/genetics ; Glycoproteins/genetics ; RNA, Messenger/metabolism ; Spinal Cord/metabolism
Chemical Substances	Glycoproteins ; RNA, Messenger
Language	English
Publishing date	2015-12
Publishing country	United States
Document type	Comment ; Letter
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2015.10.003
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Article ; Online: TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation.

Moutinho, Miguel / Coronel, Israel / Tsai, Andy P / Di Prisco, Gonzalo Viana / Pennington, Taylor / Atwood, Brady K / Puntambekar, Shweta S / Smith, Daniel C / Martinez, Pablo / Han, Seonggyun / Lee, Younghee / Lasagna-Reeves, Cristian A / Lamb, Bruce T / Bissel, Stephanie J / Nho, Kwangsik / Landreth, Gary E

Genome medicine

2023 Volume 15, Issue 1, Page(s) 11

Abstract: Background: TREM2 is a transmembrane receptor expressed by myeloid cells and acts to regulate their immune response. TREM2 governs the response of microglia to amyloid and tau pathologies in the Alzheimer's disease (AD) brain. TREM2 is also present in a ...

Abstract	Background: TREM2 is a transmembrane receptor expressed by myeloid cells and acts to regulate their immune response. TREM2 governs the response of microglia to amyloid and tau pathologies in the Alzheimer's disease (AD) brain. TREM2 is also present in a soluble form (sTREM2), and its CSF levels fluctuate as a function of AD progression. Analysis of stroke and AD mouse models revealed that sTREM2 proteins bind to neurons, which suggests sTREM2 may act in a non-cell autonomous manner to influence neuronal function. sTREM2 arises from the proteolytic cleavage of the membrane-associated receptor. However, alternatively spliced TREM2 species lacking a transmembrane domain have been postulated to contribute to the pool of sTREM2. Thus, both the source of sTREM2 species and its actions in the brain remain unclear. Methods: The expression of TREM2 isoforms in the AD brain was assessed through the analysis of the Accelerating Medicines Partnership for Alzheimer's Disease Consortium transcriptomics data, as well as qPCR analysis using post-mortem samples of AD patients and of the AD mouse model 5xFAD. TREM2 cleavage and secretion were studied in vitro using HEK-293T and HMC3 cell lines. Synaptic plasticity, as evaluated by induction of LTP in hippocampal brain slices, was employed as a measure of sTREM2 actions. Results: Three distinct TREM2 transcripts, namely ENST00000373113 (TREM2 Conclusions: TREM2 transcripts can give rise to a heterogeneous pool of sTREM2 which acts to inhibit LTP. These results provide novel insight into the generation, regulation, and function of sTREM2 which fits into the complex biology of TREM2 and its role in human health and disease. Given that sTREM2 levels are linked to AD pathogenesis and progression, our finding that sTREM2 species interfere with LTP furthers our understanding about the role of TREM2 in AD.
MeSH term(s)	Animals ; Mice ; Humans ; Long-Term Potentiation ; Alzheimer Disease/genetics ; Protein Isoforms/genetics ; Brain ; Cell Line ; Disease Models, Animal ; Membrane Glycoproteins/genetics ; Receptors, Immunologic/genetics
Chemical Substances	Protein Isoforms ; TREM2 protein, human ; Membrane Glycoproteins ; Receptors, Immunologic ; Trem2 protein, mouse
Language	English
Publishing date	2023-02-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-023-01160-z
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Article ; Online: Infiltration of inflammatory macrophages and neutrophils and widespread pyroptosis in lung drive influenza lethality in nonhuman primates.

Corry, Jacqueline / Kettenburg, Gwenddolen / Upadhyay, Amit A / Wallace, Megan / Marti, Michelle M / Wonderlich, Elizabeth R / Bissel, Stephanie J / Goss, Kyndal / Sturgeon, Timothy J / Watkins, Simon C / Reed, Douglas S / Bosinger, Steven E / Barratt-Boyes, Simon M

PLoS pathogens

2022 Volume 18, Issue 3, Page(s) e1010395

Abstract: Severe influenza kills tens of thousands of individuals each year, yet the mechanisms driving lethality in humans are poorly understood. Here we used a unique translational model of lethal H5N1 influenza in cynomolgus macaques that utilizes inhalation of ...

Abstract	Severe influenza kills tens of thousands of individuals each year, yet the mechanisms driving lethality in humans are poorly understood. Here we used a unique translational model of lethal H5N1 influenza in cynomolgus macaques that utilizes inhalation of small-particle virus aerosols to define mechanisms driving lethal disease. RNA sequencing of lung tissue revealed an intense interferon response within two days of infection that resulted in widespread expression of interferon-stimulated genes, including inflammatory cytokines and chemokines. Macaques with lethal disease had rapid and profound loss of alveolar macrophages (AMs) and infiltration of activated CCR2+ CX3CR1+ interstitial macrophages (IMs) and neutrophils into lungs. Parallel changes of AMs and neutrophils in bronchoalveolar lavage (BAL) correlated with virus load when compared to macaques with mild influenza. Both AMs and IMs in lethal influenza were M1-type inflammatory macrophages which expressed neutrophil chemotactic factors, while neutrophils expressed genes associated with activation and generation of neutrophil extracellular traps (NETs). NETs were prominent in lung and were found in alveolar spaces as well as lung parenchyma. Genes associated with pyroptosis but not apoptosis were increased in lung, and activated inflammatory caspases, IL-1β and cleaved gasdermin D (GSDMD) were present in bronchoalveolar lavage fluid and lung homogenates. Cleaved GSDMD was expressed by lung macrophages and alveolar epithelial cells which were present in large numbers in alveolar spaces, consistent with loss of epithelial integrity. Cleaved GSDMD colocalized with viral NP-expressing cells in alveoli, reflecting pyroptosis of infected cells. These novel findings reveal that a potent interferon and inflammatory cascade in lung associated with infiltration of inflammatory macrophages and neutrophils, elaboration of NETs and cell death by pyroptosis mediates lethal H5N1 influenza in nonhuman primates, and by extension humans. These innate pathways represent promising therapeutic targets to prevent severe influenza and potentially other primary viral pneumonias in humans.
MeSH term(s)	Animals ; Influenza A Virus, H5N1 Subtype ; Interferons/immunology ; Lung ; Macrophages, Alveolar/immunology ; Neutrophils/immunology ; Orthomyxoviridae Infections/immunology ; Primates ; Pyroptosis
Chemical Substances	Interferons (9008-11-1)
Language	English
Publishing date	2022-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010395
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Article ; Online: PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease.

Tsai, Andy P / Dong, Chuanpeng / Lin, Peter Bor-Chian / Messenger, Evan J / Casali, Brad T / Moutinho, Miguel / Liu, Yunlong / Oblak, Adrian L / Lamb, Bruce T / Landreth, Gary E / Bissel, Stephanie J / Nho, Kwangsik

Genome medicine

2022 Volume 14, Issue 1, Page(s) 17

Abstract: Background: Alzheimer's disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Accumulating evidence from genetic studies suggests the importance of phospholipase C γ 2 (PLCG2) in late-onset AD ( ... ...

Abstract	Background: Alzheimer's disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Accumulating evidence from genetic studies suggests the importance of phospholipase C γ 2 (PLCG2) in late-onset AD (LOAD) pathophysiology. However, the role of PLCG2 in AD is still poorly understood. Methods: Using bulk RNA-Seq (N=1249) data from the Accelerating Medicines Partnership-Alzheimer's Disease Consortium (AMP-AD), we investigated whether PLCG2 expression increased in the brains of LOAD patients. We also evaluated the relationship between PLCG2 expression levels, amyloid plaque density, and expression levels of microglia specific markers (AIF1 and TMEM119). Finally, we investigated the longitudinal changes of PLCG2 expression in the 5xFAD mouse model of AD. To further understand the role of PLCG2 in different signaling pathways, differential gene expression and co-expression network analyses were performed using bulk RNA-Seq and microglial single-cell RNA-Seq data. To substantiate the human analyses, we performed differential gene expression analysis on wild-type (WT) and inactivated Plcg2 mice and used immunostaining to determine if the differentially expressed genes/pathways were altered by microglial cell coverage or morphology. Results: We observed significant upregulation of PLCG2 expression in three brain regions of LOAD patients and significant positive correlation of PLCG2 expression with amyloid plaque density. These findings in the human brain were validated in the 5xFAD amyloid mouse model, which showed disease progression-dependent increases in Plcg2 expression associated with amyloid pathology. Of note, increased Plcg2 expression levels in 5xFAD mice were abolished by reducing microglia. Furthermore, using bulk RNA-Seq data, we performed differential expression analysis by comparing cognitively normal older adults (CN) with 75th percentile (high) and 25th percentile (low) PLCG2 gene expression levels to identify pathways related to inflammation and the inflammatory response. The findings in the human brain were validated by differential expression analyses between WT and plcg2 inactivated mice. PLCG2 co-expression network analysis of microglial single-cell RNA-Seq data identified pathways related to the inflammatory response including regulation of I-kappaB/NF-kappa B signaling and response to lipopolysaccharide. Conclusions: Our results provide further evidence that PLCG2 plays an important role in AD pathophysiology and may be a potential target for microglia-targeted AD therapies.
MeSH term(s)	Aged ; Alzheimer Disease/pathology ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Microglia/metabolism ; Phospholipase C gamma/genetics ; Phospholipase C gamma/metabolism ; Plaque, Amyloid/genetics ; Plaque, Amyloid/metabolism ; Plaque, Amyloid/pathology
Chemical Substances	PLCG2 protein, human (EC 3.1.4.3) ; Phospholipase C gamma (EC 3.1.4.3)
Language	English
Publishing date	2022-02-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-022-01022-0
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Article ; Online: Dementia exacerbates periodontal bone loss in females.

Yamada, Chiaki / Ho, Anny / Garcia, Christopher / Oblak, Adrian L / Bissel, Stephanie / Porosencova, Tatiana / Porosencov, Egor / Uncuta, Diana / Ngala, Bidii / Shepilov, Dmytro / Skibo, Galyna / Mascarenhas, Ana Karina / Akkaoui, Juliet / Lakshmana, Madepalli K / Sankar, Uma / Nichols, Frank / Lamb, Bruce T / Groppa, Stanislav / Movila, Alexandru

Journal of periodontal research

2024

Abstract: Background: Periodontitis is a chronic inflammatory disease defined by the pathologic loss of the periodontal ligament and alveolar bone in relation to aging. Although clinical cohort studies reported that periodontitis is significantly elevated in ... ...

Abstract	Background: Periodontitis is a chronic inflammatory disease defined by the pathologic loss of the periodontal ligament and alveolar bone in relation to aging. Although clinical cohort studies reported that periodontitis is significantly elevated in males compared to females, emerging evidence indicates that females with dementia are at a greater risk for periodontitis and decreased alveolar bone. Objective: This study aimed to evaluate whether dementia is a potential sex-dependent risk factor for periodontal bone loss using an experimental model of periodontitis induced in the triple transgenic (3x-Tg) dementia-like mice and clinical samples collected from senior 65 plus age patients with diagnosed dementia. Materials and methods: We induced periodontitis in dementia-like triple-transgenic (3x-Tg) male and female mice and age-matched wild-type (WT) control mice by ligature placement. Then, alveolar bone loss and osteoclast activity were evaluated using micro-CT and in situ imaging assays. In addition, we performed dental examinations on patients with diagnosed dementia. Finally, dementia-associated Aβ42 and p-Tau (T181) and osteoclastogenic receptor activator of nuclear factor kappa-Β ligand (RANKL) in gingival crevicular fluid (GCF) collected from mice and clinical samples were measured by enzyme-linked immunosorbent assay (ELISA). Results: Alveolar bone loss and in situ osteoclast activity were significantly elevated in periodontal lesions of 3x-Tg females but not males, compared to wild-type control mice. In addition, we also observed that the probing pocket depth (PPD) was also significantly elevated in female patients with dementia. Using ELISA assay, we observed that females had elevated levels of osteoclastogenic RANKL and dementia-associated Aβ42 and p-Tau (T181) in the GCF collected from experimental periodontitis lesions and clinical samples. Conclusion: Altogether, we demonstrate that females with dementia have an increased risk for periodontal bone loss compared to males.
Language	English
Publishing date	2024-01-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	390953-0
ISSN	1600-0765 ; 0022-3484
ISSN (online)	1600-0765
ISSN	0022-3484
DOI	10.1111/jre.13227
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Article ; Online: Emerging Infections of CNS: Avian Influenza A Virus, Rift Valley Fever Virus and Human Parechovirus.

Wiley, Clayton A / Bhardwaj, Nitin / Ross, Ted M / Bissel, Stephanie J

Brain pathology (Zurich, Switzerland)

2015 Volume 25, Issue 5, Page(s) 634–650

Abstract: History is replete with emergent pandemic infections that have decimated the human population. Given the shear mass of humans that now crowd the earth, there is every reason to suspect history will repeat itself. We describe three RNA viruses that have ... ...

Abstract	History is replete with emergent pandemic infections that have decimated the human population. Given the shear mass of humans that now crowd the earth, there is every reason to suspect history will repeat itself. We describe three RNA viruses that have recently emerged in the human population to mediate severe neurological disease. These new diseases are results of new mutations in the infectious agents or new exposure pathways to the agents or both. To appreciate their pathogenesis, we summarize the essential virology and immune response to each agent. Infection is described in the context of known host defenses. Once the viruses evade immune defenses and enter central nervous system (CNS) cells, they rapidly co-opt host RNA processing to a cataclysmic extent. It is not clear why the brain is particularly susceptible to RNA viruses; but perhaps because of its tremendous dependence on RNA processing for physiological functioning, classical mechanisms of host defense (eg, interferon disruption of viral replication) are diminished or not available. Effectiveness of immunity, immunization and pharmacological therapies is reviewed to contextualize the scope of the public health challenge. Unfortunately, vaccines that confer protection from systemic disease do not necessarily confer protection for the brain after exposure through unconventional routes.
MeSH term(s)	Animals ; Birds ; Central Nervous System Viral Diseases/epidemiology ; Central Nervous System Viral Diseases/pathology ; Central Nervous System Viral Diseases/virology ; Communicable Diseases, Emerging/epidemiology ; Communicable Diseases, Emerging/pathology ; Communicable Diseases, Emerging/virology ; Humans ; Influenza A virus/pathogenicity ; Influenza, Human/epidemiology ; Influenza, Human/pathology ; Influenza, Human/virology ; Orthomyxoviridae Infections/epidemiology ; Orthomyxoviridae Infections/pathology ; Orthomyxoviridae Infections/virology ; Parechovirus/pathogenicity ; Rift Valley Fever/epidemiology ; Rift Valley Fever/pathology ; Rift Valley Fever/virology
Language	English
Publishing date	2015-08-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1051484-3
ISSN	1750-3639 ; 1015-6305
ISSN (online)	1750-3639
ISSN	1015-6305
DOI	10.1111/bpa.12281
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Article ; Online: Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease.

Tsai, Andy P / Dong, Chuanpeng / Lin, Peter Bor-Chian / Oblak, Adrian L / Viana Di Prisco, Gonzalo / Wang, Nian / Hajicek, Nicole / Carr, Adam J / Lendy, Emma K / Hahn, Oliver / Atkins, Micaiah / Foltz, Aulden G / Patel, Jheel / Xu, Guixiang / Moutinho, Miguel / Sondek, John / Zhang, Qisheng / Mesecar, Andrew D / Liu, Yunlong /

Atwood, Brady K / Wyss-Coray, Tony / Nho, Kwangsik / Bissel, Stephanie J / Lamb, Bruce T / Landreth, Gary E

Immunity

2023 Volume 56, Issue 9, Page(s) 2121–2136.e6

Abstract: Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor ...

Abstract	Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2
MeSH term(s)	Animals ; Mice ; Alzheimer Disease/genetics ; Genetic Association Studies ; Microglia ; Phagocytosis/genetics ; Phenotype ; Plaque, Amyloid ; Phospholipase C gamma/metabolism
Chemical Substances	Phospholipase C gamma (EC 3.1.4.3)
Language	English
Publishing date	2023-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2023.08.008
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Article ; Online: IL-34 exacerbates pathogenic features of Alzheimer's disease and calvaria osteolysis in triple transgenic (3x-Tg) female mice.

Ho, Anny / Ngala, Bidii / Yamada, Chiaki / Garcia, Christopher / Duarte, Carolina / Akkaoui, Juliet / Ciolac, Dumitru / Nusbaum, Amilia / Kochen, William / Efremova, Daniela / Groppa, Stanislav / Nathanson, Lubov / Bissel, Stephanie / Oblak, Adrian / Kacena, Melissa A / Movila, Alexandru

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2023 Volume 166, Page(s) 115435

Abstract: Hallmark features of Alzheimer's disease (AD) include elevated accumulation of aggregated Aβ40 and Aβ42 peptides, hyperphosphorylated Tau (p-Tau), and neuroinflammation. Emerging evidence indicated that interleukin-34 (IL-34) contributes to AD and ... ...

Abstract	Hallmark features of Alzheimer's disease (AD) include elevated accumulation of aggregated Aβ40 and Aβ42 peptides, hyperphosphorylated Tau (p-Tau), and neuroinflammation. Emerging evidence indicated that interleukin-34 (IL-34) contributes to AD and inflammatory osteolysis via the colony-stimulating factor-1 receptor (CSF-1r). In addition, CSF-1r is also activated by macrophage colony-stimulating factor-1 (M-CSF). While the role of M-CSF in bone physiology and pathology is well addressed, it remains controversial whether IL-34-mediated signaling promotes osteolysis, neurodegeneration, and neuroinflammation in relation to AD. In this study, we injected 3x-Tg mice with mouse recombinant IL-34 protein over the calvaria bone every other day for 42 days. Then, behavioral changes, brain pathology, and calvaria osteolysis were evaluated using various behavioral maze and histological assays. We demonstrated that IL-34 administration dramatically elevated AD-like anxiety and memory loss, pathogenic amyloidogenesis, p-Tau, and RAGE expression in female 3x-Tg mice. Furthermore, IL-34 delivery promoted calvaria inflammatory osteolysis compared to the control group. In addition, we also compared the effects of IL-34 and M-CSF on macrophages, microglia, and RANKL-mediated osteoclastogenesis in relation to AD pathology in vitro. We observed that IL-34-exposed SIM-A9 microglia and 3x-Tg bone marrow-derived macrophages released significantly elevated amounts of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6, compared to M-CSF treatment in vitro. Furthermore, IL-34, but not M-CSF, elevated RANKL-primed osteoclastogenesis in the presence of Aβ40 and Aβ42 peptides in bone marrow derived macrophages isolated from female 3x-Tg mice. Collectively, our data indicated that IL-34 elevates AD-like features, including behavioral changes and neuroinflammation, as well as osteoclastogenesis in female 3x-Tg mice.
MeSH term(s)	Animals ; Female ; Mice ; Alzheimer Disease/metabolism ; Animals, Genetically Modified ; Interleukins ; Neuroinflammatory Diseases ; Osteolysis/metabolism ; Skull
Chemical Substances	Interleukins ; interleukin-34, mouse
Language	English
Publishing date	2023-09-04
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2023.115435
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