A high-fat diet exacerbates the Alzheimer's disease pathology in the hippocampus of the App[NL-F/NL-F] knock-in mouse model
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PROVIDER: PRJNA639606 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the effects of diabetic conditions on the development of AD pathology, we fed wild-type and Alzheimer's disease model (App[NL-F/NL-F]) mice with control or high fat diet from 6 months after birth for 12 months, then examined behavior, brain pathology and gene expression profiles. Both groups of mice fed with high fat diet exhibited diabetic conditions, and App[NL-F/NL-F] mice exhibited aggravated cognitive impairment with enhanced Alzheimer's disease pathology.
2021-06-30 | GSE152539 | GEO
Project description:While mouse models of ß-amyloidopathy recapitulate aspects of Alzheimer's disease pathology, including plaque formation and synapse loss, most progress at a speed such that outcomes are studied in the mature mouse, rather than the aged mouse. Here we investigated Aß-dependent changes to astrocytes in a knock-in model of ß-amyloidopathy (APP NL-F) that is known to progress more slowly.
2024-03-21 | E-MTAB-13936 | biostudies-arrayexpress
Project description:Bulk RNA-sequencing of astrocytes in the APP NL-F and APP PS1 models of ß-amyloidopathy, in which aspects of AD-related pathology progress at different speed, shows age-dependent gene expression changes. However, bulk RNA-seq does not provide insight into the heterogeneity of expression within this cell type, particularly relevant for such models, where reactive astrogliosis is most prominent in the vicinity of plaques. To investigate astrocyte heterogeneity in ß-amyloidopathy models, we thus performed single cell RNA-sequencing on astrocytes separated by FACS.
2024-03-21 | E-MTAB-13937 | biostudies-arrayexpress
Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a progressive cognitive decline. Epidemiological studies have suggested a protective role of caffeine consumption against age-related cognitive impairments and the risk of developing AD. Effects of caffeine have been particularly ascribed to its ability to block adenosine A2A receptors (A2ARs). Early pathological upregulation of these receptors by neurons is thought to be involved in the development of synaptic and memory deficits in AD but this remains ill-defined. To tackle this question, we employed a novel transgenic mouse model allowing to promote a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice, developing AD-like amyloidogenesis. This new model was used to determine the impact of an early upregulation of A2AR on the progression of neuropathological lesions, associated behavior and underlying mechanisms in APP/PS1 mice. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioral changes were not linked to major change in the development of amyloid pathology but rather associate with an increased p-tau at neuritic plaques. Moreover, proteomic and transcriptomic analysis coupled to quantitative immunofluorescence studies indicated that neuronal impairment of the receptor promoted both neuronal- and non-neuronal autonomous alterations i.e. loss of excitatory synapses and neuroinflammatory response, respectively, both presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction as seen in the brain of patients contributes to AD pathogenesis, favoring synaptic deficits promoted by both amyloid (this study) and tau lesions (our previous study). In addition to provide new insights into the complex pathophysiology of AD, the present findings underscore the potential of A2AR as a relevant therapeutic target for mitigating early synaptic loss in this neurodegenerative disorder.
2023-11-30 | GSE248245 | GEO
Project description:Insulin resistance and diabetes mellitus are major risk factors for Alzheimer's disease (AD), and studies with transgenic mouse models of AD have provided supportive evidence with some controversies. To overcome potential artifacts derived from transgenes, we used a knock-in mouse model, AppNL-F/NL-F , which accumulates Aβ plaques from 6 months of age and shows mild cognitive impairment at 18 months of age, without the overproduction of APP. In the present study, 6-month-old male AppNL-F/NL-F and wild-type mice were fed a regular or high-fat diet (HFD) for 12 months. HFD treatment caused obesity and impaired glucose tolerance (i.e., T2DM conditions) in both wild-type and AppNL-F/NL-F mice, but only the latter animals exhibited an impaired cognitive function accompanied by marked increases in both Aβ deposition and microgliosis as well as insulin resistance in the hippocampus. Furthermore, HFD-fed AppNL-F/NL-F mice exhibited a significant decrease in volume of the granule cell layer in the dentate gyrus and an increased accumulation of 8-oxoguanine, an oxidized guanine base, in the nuclei of granule cells. Gene expression profiling by microarrays revealed that the populations of the cell types in hippocampus were not significantly different between the two mouse lines, regardless of the diet. In addition, HFD treatment decreased the expression of the Aβ binding protein transthyretin (TTR) in AppNL-F/NL-F mice, suggesting that the depletion of TTR underlies the increased Aβ deposition in the hippocampus of HFD-fed AppNL-F/NL-F mice.
| S-EPMC8373331 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most common form of dementia, characterized by accumulation of amyloid beta (Abeta) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Abeta pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App (NL-G-F/NL-G-F) and 3xTg-AD-H mouse models. Genes commonly altered in App (NL-G-F/NL-G-F) and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App (NL-G-F/NL-G-F) cortex as Abeta amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App (NL-G-F/NL-G-F) cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Abeta amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD.
2017-12-21 | GSE92926 | GEO
Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.
2024-09-30 | GSE235179 | GEO
Project description:Single cell sequencing of astrocytes in the APP NL-F and APP PS1 models of ß-amyloidopathy
| PRJEB74068 | ENA
Project description:We examined transgenic (TG) mice expressing human APP695 bearing the double Swedish (671KM>NL) and Indiana (717V>F) amyloid precursor protein (APP) mutations. Lentiviral vectors constitutively expressing BDNF-GFP under control of the CMV/ß-actin hybrid promoter or GFP alone were injected into the entorhinal cortices of TG mice bilaterally at age 6 months, a time point by which neuropathological degeneration and cell loss are established. Age-matched wild-type littermates underwent sham surgery or injection of lentivirus expressing GFP into the entorhinal cortices bilaterally. Keywords: Treatment effect
2009-01-23 | GSE14499 | GEO
Project description:Typical western diet exacerbates dystrophic neurite pathology in APP/PS1 and APP/PS1/Tau mouse models by reducing the clustering of microglia around β-amyloid plaques
| PRJNA604773 | ENA