Searching across hundreds of databases
Genetic, epidemiologic, and biochemical evidence suggests that predisposition to Alzheimer's disease (AD) may arise from altered cholesterol metabolism, although the molecular pathways that may link cholesterol to AD phenotypes are only partially understood. Here, we perform a phenotypic screen for pTau accumulation in AD-patient iPSC-derived neurons and identify cholesteryl esters (CE), the storage product of excess cholesterol, as upstream regulators of Tau early during AD development. Using isogenic induced pluripotent stem cell (iPSC) lines carrying mutations in the cholesterol-binding domain of APP or APP null alleles, we found that while CE also regulate Aβ secretion, the effects of CE on Tau and Aβ are mediated by independent pathways. Efficacy and toxicity screening in iPSC-derived astrocytes and neurons showed that allosteric activation of CYP46A1 lowers CE specifically in neurons and is well tolerated by astrocytes. These data reveal that CE independently regulate Tau and Aβ and identify a druggable CYP46A1-CE-Tau axis in AD.
Pubmed ID: 30686764 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
A plated array of approximately 450 small molecules that have a history of use in human clinical trials. The collection was assembled by the National Institutes of Health (NIH) through the Molecular Libraries Roadmap Initiative as part of its mission to enable the use of compound screens in biomedical research. Similar collections of FDA approved drugs have proven to be rich sources of undiscovered bioactivity and therapeutic potential. The clinically tested compounds in the NCC are highly drug-like with known safety profiles. These compounds can provide excellent starting points for medicinal chemistry optimization and, for high-affinity targets, may even be appropriate for direct human use in new disease areas.
View all literature mentionsA contract research organization providing drug development and animal testing services. Under the name Covance Research Products Inc., based in Denver, Pennsylvania, the company also deals in the import, breeding and sale of laboratory animals. It breeds dogs, rabbits, guinea pigs, non-human primates, and pigs, and runs the largest non-human primate laboratory in Germany. (Wikipedia)
View all literature mentionsNEURON is a simulation environment for modeling individual neurons and networks of neurons. It provides tools for conveniently building, managing, and using models in a way that is numerically sound and computationally efficient. It is particularly well-suited to problems that are closely linked to experimental data, especially those that involve cells with complex anatomical and biophysical properties. NEURON has benefited from judicious revision and selective enhancement, guided by feedback from the growing number of neuroscientists who have used it to incorporate empirically-based modeling into their research strategies. NEURON's computational engine employs special algorithms that achieve high efficiency by exploiting the structure of the equations that describe neuronal properties. It has functions that are tailored for conveniently controlling simulations, and presenting the results of real neurophysiological problems graphically in ways that are quickly and intuitively grasped. Instead of forcing users to reformulate their conceptual models to fit the requirements of a general purpose simulator, NEURON is designed to let them deal directly with familiar neuroscience concepts. Consequently, users can think in terms of the biophysical properties of membrane and cytoplasm, the branched architecture of neurons, and the effects of synaptic communication between cells. * helps users focus on important biological issues rather than purely computational concerns * has a convenient user interface * has a user-extendable library of biophysical mechanisms * has many enhancements for efficient network modeling * offers customizable initialization and simulation flow control * is widely used in neuroscience research by experimentalists and theoreticians * is well-documented and actively supported * is free, open source, and runs on (almost) everything
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsThis monoclonal targets CD271 (NGF Receptor)
View all literature mentionsThis polyclonal targets Proteasome 20S β5 subunit (human) pAb
View all literature mentionsThis monoclonal targets p70 S6 Kinase, phospho (Thr389)
View all literature mentionsThis monoclonal targets GAPDH
View all literature mentionsThis monoclonal targets Rps27a
View all literature mentionsThis polyclonal targets p70 S6 Kinase
View all literature mentionsThis unknown targets A synthetic peptide made to the N-terminal region of the human LC3, isoform B protein.
View all literature mentionsThis polyclonal targets EIF4EBP1
View all literature mentionsThis polyclonal targets Histone H3
View all literature mentionsThis polyclonal targets 4E-BP1
View all literature mentionsThis polyclonal targets beta-Amyloid Precursor-Like Protein 2
View all literature mentionsThis polyclonal targets Human Amyloid Precursor Protein, C-Terminal (751-770)
View all literature mentionsThis monoclonal targets actin
View all literature mentionsThis monoclonal targets Alzheimer Precursor Protein A4, aa66-81 of APP
View all literature mentionsThis unknown targets Tau
View all literature mentionsThis polyclonal targets MAP2 antibody - Neuronal Marker
View all literature mentionsThis monoclonal targets Tau
View all literature mentionsThis monoclonal targets CD184
View all literature mentionsThis monoclonal targets CD44
View all literature mentionsThis polyclonal targets S100 Beta
View all literature mentionsThis unknown targets Human TRA-1-81 Antigen
View all literature mentionsThis monoclonal targets Synaptobrevin 2
View all literature mentionsCell line UCSD-SAD4.43 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD-SAD6.9 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD-SAD5.17 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD-SAD3.7 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD-SAD7D is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD-NDC5.20 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD232i-SAD2-1 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD-NDC4.43 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD229i-SAD1-1 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD-NDC3.1 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD226i-NDC2-1 is a Induced pluripotent stem cell with a species of origin Homo sapiens
View all literature mentionsCell line UCSD239i-APP2-1 is a Induced pluripotent stem cell with a species of origin Homo sapiens
View all literature mentionsCell line UCSD223i-NDC1-1 is a Induced pluripotent stem cell with a species of origin Homo sapiens
View all literature mentionsCell line UCSD236i-APP1-1 is a Induced pluripotent stem cell with a species of origin Homo sapiens
View all literature mentionsCell line CV-hIPS-B-APP-E693A clone 3d9 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line CV-hIPS-B-APP-F691A/E693A clone D12 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line CV-hIPS-B-control APP edition clone B11 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line CV-hIPS-B-APP-E693A clone 2b2 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line UCSD237i-APP1-2 is a Induced pluripotent stem cell with a species of origin Homo sapiens
View all literature mentionsCell line CV-hIPS-B is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsCell line CV-hIPS-B-control APP edition clone B10 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets CD44
View all literature mentionsThis monoclonal targets GAPDH
View all literature mentionsThe SciCrunch Infrastructure was developed as a cooperative data platform to be used by diverse communities in making data more FAIR.
scicrunch.org
