MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA970361 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24474798_1.fastq.gz | Fastqsanger.gz | |||
| SRR24474798_2.fastq.gz | Fastqsanger.gz | |||
| SRR24474799_1.fastq.gz | Fastqsanger.gz | |||
| SRR24474799_2.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Beneficial effect of an adenosine A2AR antagonist in the APPswe/PS1dE9 mouse model of Alzheimer’s Disease
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Project description:To explore the miRNAs associated with the memory deficits in Alzheimer's disease, we detected the miRNA profiles in the hippocampus of 6-month-old male APPswe/PS1dE9 (APP/PS1) mice and age-matched wild type C57BL/6 mice.
2019-10-04 | GSE138382 | GEO
Project description:Beneficial effect of an adenosine A2AR antagonist in the APPswe/PS1dE9 mouse model of Alzheimer’s Disease
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Project description:Brain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces ?-amyloid (A?) production and plaque formation after 6 weeks of treatment in 4.5-month-old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c-Jun N-terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in A? metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on A? pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.
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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.
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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+).
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Project description:To characterize the differentially expressed microRNAs between APPswe/PS1deltaE9 transgenic mice cortex and normal wild type mice cortex We isolated APPswe/PS1delataE9 and wild type mice brain cortexes for microRNA sequencing.
2015-03-05 | E-GEOD-55589 | biostudies-arrayexpress
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
Project description:Amyloid-β (Aβ) deposition in the brain has been implicated in the development of Alzheimer's disease (AD), and neuroinflammation generates AD progression. Therapeutic effects of anti-inflammatory approaches in AD are still under investigation. Curcumin, a potent anti-inflammatory and antioxidant, has demonstrated therapeutic potential in AD models. However, curcumin's anti-inflammatory molecular mechanisms and its associated cognitive impairment mechanisms in AD remain unclear. The high-mobility group box-1 protein (HMGB1) participates in the regulation of neuroinflammation. Herein, we attempted to evaluate the anti-inflammatory effects of chronic oral administration of curcumin and HMGB1 expression in APP/PS1 transgenic mice AD model. We found that transgenic mice treated with a curcumin diet had shorter escape latencies and showed a significant increase in percent alternation, when compared with transgenic mice, in the Morris water maze and Y-maze tests. Additionally, curcumin treatment could effectively decrease HMGB1 protein expression, advanced glycosylation end product-specific receptor (RAGE), Toll-like receptors-4 (TLR4) and nuclear factor kappa B (NF-κB) in transgenic mice hippocampus. However, amyloid plaques detected with thioflavin-S staining in transgenic mice hippocampus were not affected by curcumin treatment. In contrast, curcumin significantly decreased GFAP-positive cells, as assessed by immunofluorescence staining. Taken together, these data indicate that oral administration of curcumin may be a promising agent to attenuate memory deterioration in AD mice, probably inhibiting the HMGB1-RAGE/TLR4-NF-κB inflammatory signalling pathway.
| S-EPMC8435415 | biostudies-literature