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Transcriptional reprogramming by SPI1 (PU.1) modulates Alzheimer’s disease phenotypes in mouse models

ABSTRACT: SPI1 (PU.1) was recently reported as a genetic risk factor of Alzheimer’s disease (AD) in large-scale genome-wide association studies (GWAS). However, it is unknown whether PU.1 should be downregulated or increased to have therapeutic benefits. This is a critical question that must be answered before initiating any drug discovery project. To investigate the effect of modulating PU.1 level on AD pathology, we performed biochemical, histological, transcriptomic, and proteomic analyses using PU.1-knockdown and overexpression mouse models. PU.1-knockdown markedly increased amyloid-b (Ab) levels, amyloid plaque deposition, and gliosis. Conversely, PU.1-overexpression significantly decreased Ab levels, amyloid plaque deposition, gliosis, and dystrophic neurites. Furthermore, we identified several biological pathways, such as immune response pathways and complement system, regulated by the altered PU.1 expression through the analyses of proteomics as well as bulk and single-cell transcriptomics data. Our data provide crucial in vivo data to guide future therapeutic strategies for AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE222624 | GEO | 2024/03/18

REPOSITORIES: GEO

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Transcriptional reprogramming by SPI1 (PU.1) modulates Alzheimer’s disease phenotypes in mouse models

Project description:SPI1 (PU.1) was recently reported as a genetic risk factor of Alzheimer’s disease (AD) in large-scale genome-wide association studies (GWAS). However, it is unknown whether PU.1 should be downregulated or increased to have therapeutic benefits. This is a critical question that must be answered before initiating any drug discovery project. To investigate the effect of modulating PU.1 level on AD pathology, we performed biochemical, histological, transcriptomic, and proteomic analyses using PU.1-knockdown and overexpression mouse models. PU.1-knockdown markedly increased amyloid-b (Ab) levels, amyloid plaque deposition, and gliosis. Conversely, PU.1-overexpression significantly decreased Ab levels, amyloid plaque deposition, gliosis, and dystrophic neurites. Furthermore, we identified several biological pathways, such as immune response pathways and complement system, regulated by the altered PU.1 expression through the analyses of proteomics as well as bulk and single-cell transcriptomics data. Our data provide crucial in vivo data to guide future therapeutic strategies for AD.

2024-03-18 | GSE225669 | GEO

microRNA-132/212 deficiency enhances Ab production and senile plaque deposition in Alzheimerâs disease triple transgenic mice

Project description:The abnormal regulation of amyloid-b (Ab) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimerâs disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Ab deposition and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Ab metabolism, including Tau, Mapk, and Sirt1. We used RNA-Seq to analyse the hippocampus of 3xTg-AD mice lacking the miR-132/212 cluster as well as Neuro2a cells overexpressing miR-132 mimics.

2016-07-17 | E-GEOD-84481 | biostudies-arrayexpress

microRNA-132/212 deficiency enhances Ab production and senile plaque deposition in Alzheimer’s disease triple transgenic mice

Project description:The abnormal regulation of amyloid-b (Ab) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimer’s disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Ab deposition and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Ab metabolism, including Tau, Mapk, and Sirt1.

2016-07-17 | GSE84481 | GEO

Staging Alzheimer’s disease in brains and retinas of APP/PSEN1 mice by transcriptional profiling

Project description:Alzheimer’s disease (AD) is a common form of dementia characterized by amyloid plaque deposition, TAU pathology, neuroinflammation and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1) shows plaque deposition and associated neuroinflammatory responses involving both astrocytes and microglia beginning around 6 months of age. However, in our colony, TAU pathology, significant neurodegeneration and cognitive decline are not apparent in this model even at older ages. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized linear modeling (GLM), functional annotation followed by validation by immunofluorescence (IF) was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2-6 months of age).

2019-11-25 | GSE136861 | GEO

Microglial proteomic signatures in APPPS1 and APP-KI mice

Project description:Microglial dysfunction is a key pathological feature of Alzheimer´s disease (AD), but little is known about proteome-wide changes in microglia during the course of AD pathogenesis and their consequences for microglial function. Here, we performed an in-depth proteomic characterization of microglia in two AD mouse models, the overexpression APPPS1 and the knock-in AppNL-G-F (APP-KI) model. Proteome changes were followed from pre-deposition to early, middle and advanced stages of amyloid plaque pathology, revealing a large panel of Microglial Amyloid Response Proteins (MARPs) that reflect a heterogeneity of microglial alterations triggered by Adeposition. We demonstrate that the occurrence of MARPs coincided with the deposition of fibrillar A, recruitment of microglia to amyloid plaques and phagocytic dysfunction. While the proteomic and functional microglial changes were already markedly seen in 3 months old APPPS1 mice, they were delayed in the APP-KI model that generates substantially less fibrillar A. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy.

2020-06-09 | PXD016075 | Pride

Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming II

Project description:Late-onset Alzheimer’s disease (LOAD) is the most common form of AD. However, modeling sporadic LOAD, without clear genetic predispositions, to capture hallmark neuronal pathologies such as extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal loss, remains an unmet need. Here, we demonstrate that neurons generated by microRNA-based direct reprogramming of fibroblasts from patients affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional (3D) environment, effectively recapitulate key neuropathological features of AD without additional cellular or genetic insults. These LOAD neurons exhibit Aβ-dependent neurodegeneration, as treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover, inhibiting age-associated retrotransposable elements (RTEs) in LOAD neurons reduced both Ab deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency microRNA-based neuronal reprogramming.

2024-08-05 | GSE253174 | GEO

Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming

2024-08-05 | GSE252932 | GEO

Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming III

2024-08-05 | GSE267613 | GEO

Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity, in vitro.

Project description:The organic anion transporter Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1), also known as MRP1, has been demonstrated in murine models of Alzheimer's disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that it's overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the Amyloid Precursor Protein (APP), likely via indirect modulation of alpha-, beta-, and gamma-secretase activity.

2021-01-13 | GSE164642 | GEO

Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer's disease mouse model

Project description:Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Ab) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate Ab pathology in vivo is unclear. To explore the impact of Asrij on AD pathology, we deleted asrij in the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We find that Asrij depletion ameliorates cognitive impairments, Ab deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Emerging evidence indicates a critical role of microglia in influencing AD pathology. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activity. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and Akt/mTOR signaling and impedes the pro-inflammatory Disease-Associated Microglia (DAM) state. Reduced levels of pro-inflammatory cytokines and decreased STAT3 and NF-kB activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology. Our study establishes a novel role for Asrij in regulating microglial responses to Ab pathology, and could be a potential target for therapeutic intervention.

2024-07-20 | GSE272625 | GEO

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