Beneficial effect of an adenosine A2AR antagonist in the APPswe/PS1dE9 mouse model of Alzheimer’s Disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE113141 | GEO | 2019/05/18
REPOSITORIES: GEO
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Project description:Beneficial effect of an adenosine A2AR antagonist in the APPswe/PS1dE9 mouse model of Alzheimer’s Disease
| PRJNA450200 | ENA
Project description: Not available
| S-EPMC6052540 | biostudies-literature
Project description:The adenosine 2A receptor (A2AR) is expressed on regulatory T cells (Tregs), but the functional significance is currently unknown. We compared the gene expression between wild-type (WT) and A2AR knockout (KO) Tregs and between WT Tregs treated with vehicle or a selective A2AR agonist. FACS-sorted GFP positive Tregs from WT or A2AR KO FoxP3GFP mouse spleen and lymph nodes were incubated 18 hr with vehicle (DMSO), a separate set of WT Tregs were incubated with the selective A2AR agonist ATL1222 10 nM (Dogwood Pharmaceuticals, Inc.) for 18 hr prior to RNA isolation.
2012-05-31 | E-GEOD-34006 | biostudies-arrayexpress
Project description:Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and emerging evidence has shown that microRNAs (miRNAs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of amnestic mild cognitive impairment (aMCI) and AD patients. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it didn't affect the Aβ levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.
2023-05-15 | GSE231985 | GEO
Project description:Proteins involved in the Alzheimer’s disease (AD), such as amyloid precursor protein (APP) and presenilin-1 (PS1), play critical roles in early development of the central nervous system (CNS), as well as in innate immune and glial cell responses. However, it is unknown whether these alterations start on development of the CNS of carriers of APPswe and PS1dE9 mutations , associated with familial AD. Using microarray technology we studied the genome-wide gene expression profiles in the differentiated neural progenitor cells (NPCs) from wild-type (WT) and APPswe/PS1dE9 embryo telencephalon. Differential gene expression analysis indicated the occurrence of strong innate immune and glial cell responses in APPswe/PS1dE9 neurospheres, involving mainly microglial cells, inflammatory mediators and chemokines. APPswe/PS1dE9 cells expressed up to 100-fold more CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF-alpha, which was confirmed by real time PCR. The expression of activated microglia marker Iba-1 was also 20-fold upregulated in APPswe/PS1dE9 cells. The secretome of APPswe/PSldE9 differentiated NPCs increased the chemoattraction of peripheral blood mononuclear cells (PBMCs) compared to the secretome of WT cells. Taken together, our results demonstrated that neurogenic niche obtained from differentiation of embryonic APPswe/PS1dE9 neurospheres is an excellent model for AD in vitro, since this culture spontaneously presents several alterations observed in the adult-brain with this pathology. Moreover, our data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for familial AD.
2023-09-30 | GSE227002 | GEO
Project description:The adenosine 2A receptor (A2AR) is expressed on regulatory T cells (Tregs), but the functional significance is currently unknown. We compared the gene expression between wild-type (WT) and A2AR knockout (KO) Tregs and between WT Tregs treated with vehicle or a selective A2AR agonist.
2012-06-01 | GSE34006 | GEO
Project description:Understanding of the mechanism by which A2AR is regulated has been limited by difficulty in identifying the cell types that express A2AR due to a lack of robust antibodies for these receptors. To overcome this we developed an A2AR-eGFP reporter mouse and assessed the expression of A2AR during ongoing anti-tumor immune responses.
2023-10-03 | GSE230135 | GEO
Project description:Background: The p38 alpha mitogen-activated protein kinase (p38a) pathway is linked to both innate and adaptive immune responses, and as such, is currently under active investigation as a target for drug development in the context of Alzheimer’s disease (AD) and other conditions with neuroinflammatory dysfunction. While preclinical data has shown that p38a inhibition can protect against AD-associated neuropathology, the underlying mechanisms are only partially elucidated. Inhibitors of p38a may provide benefit via modulation of microglial-associated neuroinflammatory responses that contribute to the development of AD pathology. The present study tests this hypothesis by knocking out microglial p38a and assessing early-stage pathological changes. Materials and methods: Conditional knockout of microglial p38a was accomplished in 5-month-old C57BL/6J wild-type and amyloidogenic AD model (APPswe/PS1dE9) mice using a tamoxifen-inducible Cre/loxP system. Beginning at 7.5 months of age, animals underwent behavioral assessment on the open field and radial arm water maze tests, followed by collection of cortical and hippocampal tissues at 11 months. Additional endpoint measures included microglial RNA-seq analysis, quantification of pro-inflammatory cytokines, assessment of amyloid burden and plaque deposition, and characterization of microglia-plaque dynamics using a combination of ELISA, immunohistochemical, and immunofluorescent techniques. Results: Loss of microglial p38a did not alter behavioral outcomes, pro-inflammatory cytokine levels, or overall amyloid plaque burden. However, this manipulation did significantly increase hippocampal levels of soluble Abeta42 and reduce colocalization of Iba1 and 6E10 in a subset microglia in close proximity to plaques, indicating that p38a suppression may alter microglial phagocytosis. Conclusion: The data presented here suggest that rather than reducing inflammation per se, the net effect of microglial p38a inhibition in the context of AD-type amyloid pathology could be an alteration of phagocytosis and/or plaque deposition. Additionally, these results support future investigations of microglial p38a signaling at different stages of disease, as well as its relationship to phagocytic processes in this particular cell-type.
2023-06-01 | GSE222257 | GEO
Project description:Here, we studied the interaction between dietary (TWD) and genetic factors (APPswe/PS1dE9 and tau P301L mutations) and their effect on memory, brain pathology, global gene expression and on insulin-Akt-GSK3β pathway in brain of mice with four different AD-linked genetic backgrounds: wild-type (AwTw), APPswe/PS1dE9 (A+Tw), P301Ltau (AwT+), and triple transgenic (A+T+).
2020-11-24 | GSE144746 | GEO
Project description:Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction. Reactive astrocytes and microglia are associated with amyloid plaques in Alzheimer's disease (AD). Yet, not much is known about the molecular alterations underlying this reactive phenotype. To get an insight into the molecular changes underlying AD induced astrocyte and microglia reactivity, we performed a transcriptional analysis on acutely isolated astrocytes and microglia from the cortex of aged controls and APPswe/PS1dE9 AD mice. As expected, both cell types acquired a proinflammatory phenotype, which confirms the validity of our approach. Interestingly, we observed that the immune alteration in astrocytes was relatively more pronounced than in microglia. Concurrently, our data reveal that astrocytes display a reduced expression of neuronal support genes and genes involved in neuronal communication. The microglia showed a reduced expression of phagocytosis and/or endocytosis genes. Co-expression analysis of a human AD expression data set and the astrocyte and microglia data sets revealed that the inflammatory changes in astrocytes were remarkably comparable in mouse and human AD, whereas the microglia changes showed less similarity. Based on these findings we argue that chronically proinflammatory astrocyte and microglia phenotypes, showing a reduction of genes involved in neuronal support and neuronal signaling, are likely to contribute to the neuronal dysfunction and cognitive decline in AD. 2 cell types from 2 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4
2015-11-04 | E-GEOD-74615 | biostudies-arrayexpress