SEX-DEPENDENT TYPE I INTERFERON SIGNALING EXACERBATES ALZHEIMER'S PATHOLOGY
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE304521 | GEO | 2026/05/12
REPOSITORIES: GEO
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Project description:Background Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer’s disease (AD). In vitro, microglia preferentially upregulate iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of knocking down microglial iron import gene, Slc11a2, on AD-related cognitive decline and microglial transcriptional phenotype. Methods In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1Cre-ERT2;Slc11a2flfl;APP/PS1+ or – mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b+ microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted. Results DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2KD APP/PS1 females displayed significant increases in genes Enpp2, Ttr, and iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2KD cells from APP/PS1 females also exhibited decreased expression of markers related to disease-associated microglia (DAMs), such as Apoe, Ctsb, Csf1, and Hif1α. Conclusions This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in female microglia and cognitive deficits in Slc11a2KD APP/PS1 mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.
2024-07-17 | GSE269314 | GEO
Project description:In a series of slice electrophysiology experiments, we demonstrated that female APPSwe-Psen1dE9 Alzheimer's disease model mice show greater impairments in hippocampal synaptic plasticity than male mice of the same age and genotype. Female APP/PS1 mice also showed greater impairments in behavioural associative memory, higher amyloid plaque burden and increased microglial activation in the hippocampus than males at age 4-5 months. We thus profiled hippocampal mRNA from these mice to investigate the underlying molecular mechanisms. Compared to wild-type mice of the same sex, we found that female APP/PS1 mice showed a greater upregulation of microglial and inflammatory genes than males. Moreover, downregulation of genes associated with memory and plasticity was observed uniquely in female APP/PS1 mice. These data provide insight into the potential mechanisms of the greater prevalence and faster progression of AD in females.
2021-10-30 | GSE186710 | GEO
Project description:Backgroud Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder for which there is currently no cure, representing a serious clinical challenge. Lysine 2-hydroxyisobutyrylation (Khib) is a newly discovered post-translational modification that has been found to be widespread in a variety of organisms in recent years and is involved in important biometabolic processes that regulate protein function. However, it is unclear whether and how protein Khib modifications are involved in AD. This study aimed to explore the involvement of Khib in AD and its underlying mechanisms. Methods We compared a series of lysine acylation modification patterns between 9-month-old APP/PS1 mice and wild-type (WT) control mice by Western blot assays. Quantitative Khib proteomic analysis identified Khib modification proteins and key sites associated with AD. Using stereotactic brain injection, we delivered adeno- associated viruse (AAV) overexpressing Clusterin (CLU) K436R (lysine to arginine mutation at site 436, mimicking Khib deficiency) into the bilateral lateral ventricles of 9-month-old WT and APP/PS1 mice. Additionally, C8-D1A cells were infected with lentivirus carrying CLU K436 mutation. These approaches enabled functional assessment of CLU K436 khib modification in AD pathogenesis. Furthermore, co-immunoprecipitation analyses revealed that CLU K436 khib modification modulates the interaction between CLU and Aβ. Results The level of Khib was significantly increased in 9-month-old APP/PS1 mice. Quantitative Khib analysis identified Clusterin (CLU) as a differentially modified protein, with K436 serving as its primary Khib modification site. Further investigation revealed that CLU K436 Khib levels was upregulated in APP/PS1 AD model mice. Loss of K436 Khib in CLU K436R mutant APP/PS1 mice notably ameliorated β-amyloid plaque, gliosis, and neuroinflammation, consequently mitigating memory deficits in vivo. The lentiviral vector carrying CLU K436R mutant in C8-D1A astrocyte cell enhanced glial cell activation and cell survival in vitro. Mechanistically, CLU K436 Khib modification may affect Aβ metabolism by impacting the interaction between CLU and Aβ. Conclusions Our results indicated the role of Khib in AD, elucidating the function and potential molecular mechanism of CLU K436 Khib modification in AD. These findings offer novel perspectives on therapeutic approaches for AD.
2026-03-04 | PXD066261 | Pride
Project description:Alzheimer’s disease is known to alter astrocytes, but the effect of Aß and Tau pathology on these cells remains poorly understood. We investigated the transcriptomic behaviour of astrocytes (via translating ribosome affinity purification (TRAP)), and bulk brain tissue, in mouse models of APP/PS1 ß-amyloidopathy and MAPT-P301S tauopathy, in a mouse model overexpressing cytoprotective Nrf2 specifically in astrocytes (GFAP-Nrf2 model), and in crosses between the amyloidopathy and tauopathy models with the GFAP-Nrf2 mouse.
2021-12-02 | E-MTAB-10985 | 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:The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) in the mouse Alzheimer's Disease (AD) model APP/PS1. KD significantly rescued Long-Term-Potentiation (LTP) to wild-type levels, not by changing Amyloid-β (Aβ) levels. KD's 'main actor' is thought to be Beta-Hydroxy-butyrate (BHB) whose levels rose significantly in KD vs. CD mice, and BHB itself significantly rescued LTP in APP/PS1 hippocampi. KD's 6 most significant pathways induced in brains by RNAseq all related to Synaptic Plasticity. KD induced significant increases in synaptic plasticity enzymes p-ERK and p-CREB in both sexes, and of brain-derived neurotrophic factor (BDNF) in APP/PS1 females. We suggest KD rescues LTP through BHB's enhancement of synaptic plasticity. LTP falls in Mild-Cognitive Impairment (MCI) of human AD. KD and BHB, because they are an approved diet and supplement respectively, may be most therapeutically and translationally relevant to the MCI phase of Alzheimer's Disease.
2023-12-31 | GSE230469 | GEO
Project description:The assay for transposase-accessible chromatin by sequencing (ATAC-seq) was used to investigate the AD-associated chromatin reshaping in the APPswe/PS1dE9 (APP/PS1) mouse model. ATAC-seq data in the hippocampus of 8-month-old APP/PS1 mice were generated, and the relationship between chromatin accessibility and gene expression was analyzed in combination with RNA-sequencing.We identified 1690 increased AD-associated chromatin accessible regions in the hippocampal tissues of APP/PS1 mice and 1003 decreased chromatin accessible regions were considered to be related with declined AD-associated biological processes.In the APP/PS1 hippocampus, 1090 genes were found to be up-regulated and 1081 down-regulated. Interestingly, enhanced ATAC-seq signal was found in approximately 740 genes, with 43 exhibiting up-regulated mRNA levels.Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.
2020-07-09 | GSE145907 | GEO
Project description:The assay for transposase-accessible chromatin by sequencing (ATAC-seq) was used to investigate the AD-associated chromatin reshaping in the APPswe/PS1dE9 (APP/PS1) mouse model. ATAC-seq data in the hippocampus of 8-month-old APP/PS1 mice were generated, and the relationship between chromatin accessibility and gene expression was analyzed in combination with RNA-sequencing.We identified 1690 increased AD-associated chromatin accessible regions in the hippocampal tissues of APP/PS1 mice and 1003 decreased chromatin accessible regions were considered to be related with declined AD-associated biological processes.In the APP/PS1 hippocampus, 1090 genes were found to be up-regulated and 1081 down-regulated. Interestingly, enhanced ATAC-seq signal was found in approximately 740 genes, with 43 exhibiting up-regulated mRNA levels.Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.
2020-07-09 | GSE145906 | GEO
Project description:Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting memory and cognition. The disease is accompanied by an abnormal deposition of ß-amyloid plaques in the brain that contributes to neurodegeneration and is known to induce glial inflammation. Studies in the APP/PS1 mouse model of ß-amyloid-induced neuropathology have suggested a role for inflammasome activation in ß-amyloid-induced neuroinflammation and neuropathology. Here, we evaluated the in vivo role of microglia-selective and full body inflammasome signalling in several mouse models of ß-amyloid-induced AD neuropathology. Unexpectedly, microglia-specific deletion of the inflammasome regulator A20 and inflammasome effector protease caspase-1 in the AppNL-G-F and APP/PS1 models failed to identify a prominent role for microglial inflammasome signalling in ß-amyloid-induced neuropathology. Moreover, global inflammasome inactivation through respectively full body deletion of caspases 1 and 11 in AppNL-G-F mice and Nlrp3 deletion in APP/PS1 mice, also failed to modulate amyloid pathology and disease progression. In agreement, single-cell RNA sequencing did not reveal an important role for Nlrp3 signalling in driving microglial activation and the transition into disease-associated states, both during homeostasis and upon amyloid pathology. Collectively, these results question a generalizable role for inflammasome activation in pre-clinical amyloid-only models of neuroinflammation.
2024-01-17 | GSE249611 | GEO
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