scholarly journals Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer’s Disease Not Evident in Mouse Models

Cell Reports ◽  
2018 ◽  
Vol 22 (3) ◽  
pp. 832-847 ◽  
Author(s):  
Brad A. Friedman ◽  
Karpagam Srinivasan ◽  
Gai Ayalon ◽  
William J. Meilandt ◽  
Han Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Microglial Activation ◽  
Expression Profiles

scholarly journals Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

2020 ◽  
Author(s):  
Nader Morshed ◽  
William T. Ralvenius ◽  
Alexi Nott ◽  
L. Ashley Watson ◽  
Felicia H. Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Response ◽  
Mouse Models ◽  
Microglial Activation ◽  
Phosphorylation Site ◽  
Amyloid Β ◽  
Similar Response ◽  
List Type ◽  
Reactive Microglia

SummaryAlzheimer’s disease (AD) is characterized by the appearance of amyloid-β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV-2 cell line and human stem-cell derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells. Collectively, our results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration.HighlightsPhosphoproteomics analysis of CK-p25, 5XFAD, and Tau P301S mouse models finds dysregulated signaling networks associated with Alzheimer’s disease pathologies.A phosphorylation site on Siglec-F is found to be upregulated across all three models of disease.Expression of Siglec-F and its human paralog Siglec-8 is increased in reactive microglia.Overexpression of Siglec-F and Siglec-8 in vitro drives an endocytic and pyroptotic inflammatory response.In BriefPhosphoproteome signaling changes associated with Alzheimer’s disease (AD) are poorly characterized. Here, Morshed et al. apply phosphoproteomics to mouse models of AD to uncover a novel microglial receptor, Siglec-F, that is upregulated on a subset of inflammatory microglia across models of neurodegeneration. The human paralog, Siglec-8 is also found to be upregulated in late-onset AD microglia. Overexpression of Siglec-F and related human Siglecs activates pro-inflammatory signaling responses in BV-2 cells.

scholarly journals Pinpointing Brain TREM2 Levels in Two Mouse Models of Alzheimer’s Disease

2021 ◽  
Author(s):  
Silvio R. Meier ◽  
Dag Sehlin ◽  
Greta Hultqvist ◽  
Stina Syvänen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Microglial Activation ◽  
Bispecific Antibody ◽  
Ex Vivo ◽  
Transgenic Animals ◽  
The Brain

Abstract Purpose The triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by brain microglia. Microglial activation, as observed in Alzheimer’s disease (AD) as well as in transgenic mice expressing human amyloid-beta, appears to increase soluble TREM2 (sTREM2) levels in CSF and brain. In this study, we used two different transgenic mouse models of AD pathology and investigated the potential of TREM2 to serve as an in vivo biomarker for microglial activation in AD. Procedures We designed and generated a bispecific antibody based on the TREM2-specific monoclonal antibody mAb1729, fused to a single-chain variable fragment of the transferrin receptor binding antibody 8D3. The 8D3-moiety enabled transcytosis of the whole bispecific antibody across the blood-brain barrier. The bispecific antibody was radiolabeled with I-125 (ex vivo) or I-124 (PET) and administered to transgenic AD and wild-type (WT) control mice. Radioligand retention in the brain of transgenic animals was compared to WT mice by isolation of brain tissue at 24 h or 72 h, or with in vivo PET at 24 h, 48 h, and 72 h. Intrabrain distribution of radiolabeled mAb1729-scFv8D3CL was further studied by autoradiography, while ELISA was used to determine TREM2 brain concentrations. Results Transgenic animals displayed higher total exposure, calculated as the AUC based on SUV determined at 24h, 48h, and 72h post injection, of PET radioligand [124I]mAb1729-scFv8D3CL than WT mice. However, differences were not evident in single time point PET images or SUVs. Ex vivo autoradiography confirmed higher radioligand concentrations in cortex and thalamus in transgenic mice compared to WT, and TREM2 levels in brain homogenates were considerably higher in transgenic mice compared to WT. Conclusion Antibody-based radioligands, engineered to enter the brain, may serve as PET radioligands to follow changes of TREM2 in vivo, but antibody formats with faster systemic clearance to increase the specific signal in relation to that from blood in combination with antibodies showing higher affinity for TREM2 must be developed to further progress this technique for in vivo use.

scholarly journals Microglial activation in vivo is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of Alzheimer’s disease

2020 ◽  
Vol 16 (S4) ◽  
Author(s):  
Gloria Biechele ◽  
Nicolai Franzmeier ◽  
Michael Ewers ◽  
Tanja Blume ◽  
Florian Eckenweber ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Microglial Activation ◽  
Tau Pathology

scholarly journals CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models

2010 ◽  
Vol 177 (5) ◽  
pp. 2549-2562 ◽  
Author(s):  
Sungho Lee ◽  
Nicholas H. Varvel ◽  
Megan E. Konerth ◽  
Guixiang Xu ◽  
Astrid E. Cardona ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Microglial Activation ◽  
Beta Amyloid ◽  
Amyloid Deposition

Anti-amnesic effect of pseudoginsenoside-F11 in two mouse models of Alzheimer's disease

2013 ◽  
Vol 106 ◽  
pp. 57-67 ◽  
Author(s):  
Chun-Ming Wang ◽  
Ming-Yan Liu ◽  
Fang Wang ◽  
Min-Jie Wei ◽  
Shuang Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Amnesic Effect

scholarly journals Oleic Acid Ameliorates Amyloidosis in Cellular and Mouse Models of Alzheimer's Disease

2010 ◽  
Vol 21 (3) ◽  
pp. 321-329 ◽  
Author(s):  
Zareen Amtul ◽  
David Westaway ◽  
David F. Cechetto ◽  
Richard F. Rozmahel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oleic Acid ◽  
Mouse Models
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