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GSAP regulates mitochondrial function through Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

ABSTRACT: Gamma-secretase activating protein (GSAP) plays an important role in regulating gamma-secretase activity and specificity, which contributes to the pathogenesis of Alzheimer’s disease (AD) and Down syndrome. GSAP is expressed in a variety of cell types in the bain. To elucidate the molecular function of GSAP across different cell types in the brain, we performed single nuclei RNA sequencing (sn-RNAseq) on hippocampal tissues obtained from wildtype (WT) and GSAP knockout (GKO) mice. To further investigate the pathogenic function of GSAP in the AD progression, we also determined effects of GSAP gene deletion in the J20 AD mouse model through sn-RNAseq on hippocampal tissues obtained from J20;WT and J20;GKO mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE157985 | GEO | 2021/05/27

REPOSITORIES: GEO

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In vivo mouse microglia scRNA seq

Project description:To address the question of whether γ-secretase deficiency affects the tonic signaling in microglia in vivo as well, we analyzed the single-cell transcriptomes of the γ-secretase deficient microglia from WT and AD mouse models at 3 ,6 and 7 months of age. Like the in vitro observations, genetic knockout of γ-secretase induced mild changes to the transcriptomes of in vivo microglia in the WT mice and also AD mice at 3 months. However, The relative proportions of DAM, CRM and TRM were significantly reduced in AppNL-G-F-GSiΔMG mice compared to AppNL-G-F-GSWT mice at 7 months, whereas HM and tCRM were significantly increased. Thus γ-secretase has a crucial role in the microglial transition from the homeostatic to the full DAM phenotype in AD.

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Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease

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Functional Interaction between APOE4 and mutant APP promotes cerebrovascular changes in young animals

Project description:The Apolipoprotein E4 (ApoE4) allele is one of the strongest risk factors for late-onset Alzheimer’s disease (AD) and is associated with a breakdown of the blood-brain barrier and vascular dysfunction (Nation et al 2019; Liu and Bu 2022). Importantly, these vascular pathologies are exacerbated when APOE4 is coexpressed with familial mutations in APP or components of the γ-secretase complex (Montagne and Zlokovic 2021), suggesting that the interactions between APOE4 and AD mutations can drive progression of the disease. However, most studies have been done in aging animals and few look at the impact of APOE4 expression in young animals and how that potentially contributes toward late-stage disease susceptibility. Here, we examined the potential functional interaction between APP mutations and ApoE4 in the progression of AD pathophysiology by comparing the hippocampal transcriptomes of 3-month-old female mice of 4 different genotypes: AppNL-G-F/NL-G-F , which harbours three knock-in mutations in the humanised Aβ region of APP (APP-TKI; Saito et al., 2014), mice with a single allele of human ApoE4 knocked-in, ApoE4+/wt (ApoE4), crosses of these two mouse lines, to create AppNL-G-F/NL-G-F;Apoe4+/wt (double-mutant or DM) mice, and wild-type (WT) mice that served as controls. RNAseq revealed nascent microglial activation signatures in both APP-TKI and double mutant datasets, as well as subtle but significant differences between APP-TKI and double mutant in expression of a subset of vascular remodeling genes.

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CHO cells with enhanced and abolished gamma-secretase activity

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Gene expression profiles of desmoid tumor cells treated with gamma-secretase inhibitor

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2015-11-03 | GSE61097 | GEO

Testosterone-dependent and independent transcriptional networks in the hypothalamus of Gpr54 and Kiss1 knockout male mice

Project description:Humans and mice with loss of function mutations in GPR54 (KISS1R) or kisspeptin (KISS1) do not progress through puberty, caused by a failure to release GnRH. The transcriptional networks regulated by these proteins in the hypothalamus have yet to be explored by genome-wide methods. Using micro-dissected hypothalamic tissues to isolate RNA from our mice, we first set out to define the transcriptional differences among the wild type and knockout mice. Since the GPR54-kisspeptin axis is subject to hormonal feedback and the knockout mice are pre-pubertal, we also tested the hormonal dependence/independence of each differentially expressed transcript. To avoid variation in gene expression due to fluctuations in the levels of circulating hormones during the female estrous cycle, only male mice were used in this study. 17 samples were successfully hybridized; 4 GKO, 5 KKO, 3 WT 3 weeks old, 5 WT 6 weeks old. We compared GKO to KKO, GKO to WT, KKO to WT and all KO to all WT.

2011-08-21 | E-GEOD-28383 | biostudies-arrayexpress

Gibbin (AHDC1) mesodermal regulation controls epithelial patterning

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