Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE206102 | GEO | 2023/08/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Induced pluripotent stem cell-derived models of sporadic and familial Alzheimer’s disease

Project description:Our understanding of Alzheimer’s disease (AD) pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of AD. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). We reprogrammed primary fibroblasts from two patients with familial AD (both caused by a duplication of APP1, APPDp), two with sporadic AD (sAD1, 2) and two non-demented control individuals (NDCs) into iPSC lines. Neurons from differentiated cultures were FACS-purified and characterized. Purified cultures contained >90% neurons, clustered with fetal brain mRNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APPDp patients and patient sAD2 exhibited significantly higher levels of secreted Aβ1-40, phospho-tauThr231 (pTau) and active GSK3β (aGSK3β). Neurons from APPDp and sAD2 patients also accumulated large Rab5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not g-secretase inhibitors, caused significant reductions in pTau and aGSK3β levels. These results suggest a direct relationship between APP proteolytic processing, but not Aβ, in GSK3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial AD samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to AD, even though it can take decades for overt disease to manifest in patients. Total RNA extracted from normal hIPSCs, Alzheimer's patient derived hIPSCs, neurons differentiated from hIPSCs, fetal brain, fetal heart, fetal liver and fetal lung

2012-01-06 | E-GEOD-34879 | biostudies-arrayexpress

Probing sporadic and familial Alzheimer?s disease using induced pluripotent stem cells.

2012-01-06 | GSE34879 | GEO

Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease

Project description:While amyloid-β (Aβ) plaques are considered a hallmark of Alzheimer's disease, clinical trials focused on targeting gamma secretase, an enzyme involved in aberrant Aβ peptide production, have not led to amelioration of AD symptoms or synaptic dysregulation. Screening strategies based on mechanistic, multi-omics approaches that go beyond pathological readouts can aid in the evaluation of therapeutics. Using early-onset Alzheimer's (EOFAD) disease patient lineage PSEN1A246E iPSC-derived neurons, we performed RNA-seq to characterize AD-associated endotypes, which are in turn used as a screening evaluation metric for two gamma secretase drugs, the inhibitor Semagacestat and the modulator BPN-15606.

2022-01-27 | GSE95673 | GEO

The γ-secretase substrate proteome and its role in cell signaling regulation

Project description:γ-Secretase is involved in the regulated intramembrane proteolysis (RIP) of a variety of integral membrane proteins and generates the amyloid peptide (Aβ) in Alzheimer’s Disease (AD). Microglia are centrally involved in AD, but the substrates and function of γ-secretase in these cells remain largely unstudied. Using a novel γ-Secretase Substrate Identification (G-SECSI) method, we identified 85 substrates, of which 59 were previously unknown, in stem cell derived microglia-like cells. More than 60% of those are signalling receptors possibly involved in cell state regulation. Inhibition of γ-secretase using Semagacestat or selective genetic knockout alters the expression of homeostatic (HM) and disease-associated (DAM) genes, in particular when microglia are exposed to amyloid plaques in vivo. Thus, γ-secretase regulates tonic signaling via a spectrum of substrates in microglia in steady state, and its blockage results in the defective transition to the DAM response in AD.

2023-11-14 | PXD039238 | Pride

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.

2023-10-20 | GSE245391 | GEO

Increase in membrane cholesterol of neurons in culture recapitulates AlzheimerM-bM-^@M-^Ys disease early phenotypes.

Project description:Levels of membrane-associated cholesterol were shown to be increased in the brain of individuals with sporadic AlzheimerM-bM-^@M-^Ys disease (AD) and correlated with the severity of the disease. We previously found that heavy membrane cholesterol burden promotes amyloid precursor protein (APP) endocytosis and processing, leading to increased amyloid-M-oM-^AM-"M-oM-^@M- M-oM-^@M-(AM-oM-^AM-") secretion. We hypothesized that such an increase of cholesterol could trigger sporadic AD. We thus acutely loaded the plasma membrane of neurons in culture with cholesterol to reach the 30 % increase observed in AD brains. We showed by multiplex electro-chemiluminescence immuno-assay that transient membrane cholesterol loading produced a significant increase of AM-oM-^AM-"42 secretion. We also found that early endosomes were enlarged and more prone to aggregation using confocal and electron microscopy and that APP vesicular transport in neuronal processes was slowed down using fluorescence live-imaging. In addition, treatment of neurons with cholesterol induced changes in gene expression profile that are reminiscent of early AD. This model of membrane cholesterol increase in cultured neurons reproduces most of early AD changes and could thus be relevant for deciphering early mechanisms and design new targets for sporadic AD. In this study, we loaded the plasma membrane of neurons with 30% more cholesterol and observed the effects on gene expression. We compared gene expression of primary hippocampal neurons treated or not with cholesterol using 4 independant replicates in each group.

2015-01-15 | E-GEOD-46221 | biostudies-arrayexpress

Effects of nicastrin (NCSTN) siRNA knockdown in HEK293 and HEK001 cells.

Project description:The goal of this study was to determine if knockdown of nicastrin induced a proinflammatory phenotype in HEK001 and HEK293 cells. Nicastrin (NCSTN) is a member of the gamma-secretase complex, and has been identified as the most frequently mutated gene in familial hidradenitis suppurativa. While much research has been done into the effects of PSEN1 and PSEN2 loss, less is known about isolated NCSTN haploinsufficiency. Two cell lines were knocked down with either NCSTN siRNA or an siRNA to luciferase in triplicate. RNA was extracted from drug selected knockdowns and profiled on the Illumina Human HT-12 v4 beadarray. Gene ontology analysis of differentially expressed genes revealed a proinflammatory and decreased proliferation signature in keratinocytes. HEK293 cells demonstrated expression signatures for decreased cholesterol synthesis and interferon-alpha signaling, as well as increased p53 signaling and caspase mediated cytoskeletal cleavage. 12 total samples. Two cell lines (HEK001 & HEK293) each with two treatments (NCSTN siRNA knockdown or pLKO luciferase knockdown) in three parallel 3 replicates each. For each line gives the changes specific to knockdown of gamma-secretase component nicastrin (NCSTN).

2014-11-26 | E-GEOD-57949 | biostudies-arrayexpress

Increase in membrane cholesterol of neurons in culture recapitulates Alzheimer’s disease early phenotypes.

Project description:Levels of membrane-associated cholesterol were shown to be increased in the brain of individuals with sporadic Alzheimer’s disease (AD) and correlated with the severity of the disease. We previously found that heavy membrane cholesterol burden promotes amyloid precursor protein (APP) endocytosis and processing, leading to increased amyloid-A) secretion. We hypothesized that such an increase of cholesterol could trigger sporadic AD. We thus acutely loaded the plasma membrane of neurons in culture with cholesterol to reach the 30 % increase observed in AD brains. We showed by multiplex electro-chemiluminescence immuno-assay that transient membrane cholesterol loading produced a significant increase of A42 secretion. We also found that early endosomes were enlarged and more prone to aggregation using confocal and electron microscopy and that APP vesicular transport in neuronal processes was slowed down using fluorescence live-imaging. In addition, treatment of neurons with cholesterol induced changes in gene expression profile that are reminiscent of early AD. This model of membrane cholesterol increase in cultured neurons reproduces most of early AD changes and could thus be relevant for deciphering early mechanisms and design new targets for sporadic AD.

2015-01-15 | GSE46221 | GEO

APP and its intracellular domain modulate Alzheimer’s disease risk gene networks in transgenic APPsw and PSEN1M146I porcine models [fibroblasts]

Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most frequent cause of dementia. The disease has a substantial genetic component comprising both highly penetrant familial mutations (APP, PSEN1 and PSEN2) and sporadic cases with complex genetic etiology. Mutations in APP and PSEN1/2 alter the proteolytic processing of APP to its metabolites, including Ab and APP Intracellular Domain (AICD). In this study, we use transgenic porcine models carrying the human APPsw and PSEN1M146I transgenes to demonstrate the pathobiological relevance of transcriptional regulation facilitated by APP and its AICD domain. Through molecular characterization of hippocampal tissue, we describe the differential expression of gene sets that cluster in molecular pathways with translational relevance to AD. We further identify phosphorylated and unphosphorylated AICD in differential complexes with proteins implicated in signal transduction and transcriptional regulation. Integrative genomic analysis of transcriptional changes in somatic cell cultures derived from pigs treated with g-secretase inhibitor demonstrates the importance of g-secretase APP processing in transcriptional regulation. Collectively, our data supports a model in which APP, and in particular its AICD domain, modulates gene networks associated with AD pathobiology through interaction with signaling proteins.

2024-02-04 | GSE254570 | GEO

APP and its intracellular domain modulate Alzheimer’s disease risk gene networks in transgenic APPsw and PSEN1M146I porcine models [hippocampus]

2024-02-04 | GSE254548 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data