scholarly journals Imbalance in the response of pre- and post-synaptic components to amyloidopathy

2019 ◽  
Author(s):  
Terri-Leigh Stephen ◽  
Francesco Tamagnini ◽  
Judith Piegsa ◽  
Katherine Sung ◽  
Joshua Harvey ◽  
...  
Keyword(s):  
Mouse Model ◽  
Synaptic Dysfunction ◽  
Functional Impairments ◽  
Synaptic Terminals ◽  
Diffuse Part ◽  
Initial Area ◽  
Synapse Density ◽  
Synaptic Dynamics ◽  
Underlying Pathology ◽  
Over Time

AbstractAlzheimer’s disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Aβ species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aβ plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aβ plaques grow faster in the earlier stages of the disease and if their initial area is > 500 µm2; this may be due to deposition occurring in the diffuse part of the plaque. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre-but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics.

scholarly journals Imbalance in the response of pre- and post-synaptic components to amyloidopathy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Terri-Leigh Stephen ◽  
Francesco Tamagnini ◽  
Judith Piegsa ◽  
Katherine Sung ◽  
Joshua Harvey ◽  
...  
Keyword(s):  
Mouse Model ◽  
Amyloid Β ◽  
Synaptic Dysfunction ◽  
Functional Impairments ◽  
Synaptic Terminals ◽  
Initial Area ◽  
Synapse Density ◽  
Synaptic Dynamics ◽  
Underlying Pathology ◽  
Over Time

Abstract Alzheimer’s disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Amyloid β (Aβ) species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aβ plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aβ plaques grow faster in the earlier stages of the disease and if their initial area is >500 µm2; this may be due to deposition occurring in the outer regions of the plaque, the plaque cloud. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre- but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics.

scholarly journals An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3

2019 ◽  
Author(s):  
Jillian M. Richmond ◽  
Dhrumil Patel ◽  
Tomoya Watanabe ◽  
Colton J. Garelli ◽  
Madhuri Garg ◽  
...  
Keyword(s):  
Mouse Model ◽  
Localized Scleroderma ◽  
Lesional Skin ◽  
Chemokine Expression ◽  
Inflammatory Phase ◽  
Deficient Mice ◽  
Over Time ◽  
Cutaneous Fibrosis

AbstractMorphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. We first characterized which cells produce the CXCR3 ligands in the skin using the Reporter of Expression of CXCR3 ligands mouse (REX3). We found that fibroblasts contribute the bulk of CXCL9 and CXCL10, whereas endothelial cells are key dual chemokine producers. Macrophages, which have high MFI of chemokine expression, upregulated CXCL9 production over time, fibroblasts CXCL10 production, and T cells dual chemokine expression. To determine whether bleomycin treatment could directly induce expression of these chemokines, we treated cultured REX3 mouse dermis monolayers in vitro with bleomycin or IFNγ with TNF and found that bleomycin could induce low amounts of CXCL9 directly in fibroblasts, whereas the cytokines were required for optimal CXCL9 and CXCL10 production. To determine whether these chemokines are mechanistically involved in pathogenesis, we induced fibrosis in CXCL9, CXCL10, or CXCR3 deficient mice and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9, but not CXCL10, to cultured mouse fibroblasts induces collagen 1a1 mRNA expression, indicating the chemokine itself can contribute to fibrosis. Taken together, our studies provide evidence that acute intradermal bleomycin administration in mice can model inflammatory morphea, and that CXCL9 and its receptor CXCR3 are mechanistically involved in pathogenesis.One Sentence SummaryCXCL9 drives acute morphea pathogenesis in mice.

scholarly journals Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

Aging Cell ◽  
2018 ◽  
Vol 17 (4) ◽  
pp. e12791 ◽  
Author(s):  
David Baglietto-Vargas ◽  
Gilberto Aleph Prieto ◽  
Agenor Limon ◽  
Stefania Forner ◽  
Carlos J. Rodriguez-Ortiz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Synaptic Dysfunction ◽  
Model Of Alzheimer’S Disease

P1-049: Chronic Memantine administration reduces APP expression, normalizes glutamatergic synapse density, and improves spatial learning in the Ts65Dn mouse model for down syndrome

2008 ◽  
Vol 4 ◽  
pp. T220-T220
Author(s):  
Carmen Martı́nez-Cué ◽  
Noemı́ Rueda ◽  
Marı́a Llorens-Martı́n ◽  
Jesús Flórez ◽  
Elsa Valdizán ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Spatial Learning ◽  
Glutamatergic Synapse ◽  
Ts65dn Mouse ◽  
Synapse Density

scholarly journals Deficits in hippocampal-dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis

Hippocampus ◽  
2015 ◽  
Vol 26 (4) ◽  
pp. 455-471 ◽  
Author(s):  
Karienn S. Montgomery ◽  
George Edwards ◽  
Yona Levites ◽  
Ashok Kumar ◽  
Catherine E. Myers ◽  
...  
Keyword(s):  
Mouse Model ◽  
Synaptic Dysfunction

scholarly journals Stochastic changes over time and not founder effects drive cage effects in microbial community assembly in a mouse model

2013 ◽  
Vol 7 (11) ◽  
pp. 2116-2125 ◽  
Author(s):  
Jonathan McCafferty ◽  
Marcus Mühlbauer ◽  
Raad Z Gharaibeh ◽  
Janelle C Arthur ◽  
Ernesto Perez-Chanona ◽  
...  
Keyword(s):  
Microbial Community ◽  
Mouse Model ◽  
Community Assembly ◽  
Founder Effects ◽  
Changes Over Time ◽  
Microbial Community Assembly ◽  
Cage Effects ◽  
Over Time

A Murine AML Model for the Development of Resistance to NRAS(G12V) Oncogene Repression and/or Ara-C Treatment in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4030-4030
Author(s):  
Won-IL Kim ◽  
Susan K Rathe ◽  
Miechaleen D Diers ◽  
David A Largaespada
Keyword(s):  
Gene Expression ◽  
Drinking Water ◽  
Mouse Model ◽  
Transplant Recipients ◽  
Conventional Chemotherapy ◽  
Ras Pathway ◽  
Development Of Resistance ◽  
Mrna Microarray ◽  
Over Time

Abstract We previously reported the development of a model of AML in mice induced by the combined expression of a conditionally expressed NRASG12V oncogene and the MLL fusion oncogene MLL-AF9. This mouse model combines a Vav promoter-Tet transactivator (Vav-tTA) transgene, a doxycycline (DOX)-repressible tet-regulated element promoter-NRASG12V (TRE-NRASG12V) transgene, and Mll-AF9 “knock-in” transgene. When we transplanted triple transgenic Vav-tTA; TRE-NRASG12V; Mll-AF9 AML into SCID mice we found that doxycycline (DOX) treatment via the drinking water could prevent AML engraftment or eliminate AML cells after growth to full-blown leukemia. However, these mice eventually develop DOX-resistant AML, which does not re-express the NRASG12V transgene. In more recent data, we find that the Vav-tTA; TRE-NRASG12V; Mll-AF9 AML cells are also Ara-C sensitive as we can repeatedly induce temporary remission in transplant recipients of these cells by 5 day courses of 50 mg/kg Ara-C given once per day intra-peritoneally. Although Ara-C is the backbone of human Ara-C treatment, many patients develop Ara-C resistant AML over time. In our model, fully Ara-C resistant AML develops after 4 to 5 courses of treatment. Nevertheless, a combination of Ara-C treatment and NRASG12V transgene suppression using DOX can extend remission and survival compared to treatment with either approach alone suggesting that some benefit could be obtained by combining RAS pathway inhibitors with conventional chemotherapy. However, even in this case, AML that is resistant to both Ara-C and NRASG12V transgene suppression eventually develops in all mice. Primary AML samples that have been selected in vivo for resistance to Ara-C, NRASG12V oncogene suppression, or both, have been collected and are being analyzed by mRNA microarray for changes in gene expression that might be responsible for the acquisition of resistance.

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