7 research outputs found
On the Low Surface Magnetic Field Structure of Quark Stars
Following some of the recent articles on hole super-conductivity and related
phenomena by Hirsch \cite{H1,H2,H3}, a simple model is proposed to explain the
observed low surface magnetic field of the expected quark stars. It is argued
that the diamagnetic moments of the electrons circulating in the electro-sphere
induce a magnetic field, which forces the existing quark star magnetic flux
density to become dilute. We have also analysed the instability of
normal-superconducting interface due to excess accumulation of magnetic flux
lines, assuming an extremely slow growth of superconducting phase through a
first order bubble nucleation type transition.Comment: 24 pages REVTEX, one .eps figure, psfig.sty is include
Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.
BACKGROUND: Genetic mutations underlying familial Alzheimer\u27s disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain.
METHODS: We engineered a novel App knock-in mouse model (App
RESULTS: Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The App
DISCUSSION: Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology
Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis
Dual leucine zipper kinase (DLK) and leucine zipper-bearing
kinase
(LZK) are regulators of neuronal degeneration and axon growth. Therefore,
there is a considerable interest in developing DLK/LZK inhibitors
for neurodegenerative diseases. Herein, we use ligand- and structure-based
drug design approaches for identifying novel amino-pyrazine inhibitors
of DLK/LZK. DN-1289 (14), a potent and selective dual
DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life
across species and is anticipated to freely penetrate the central
nervous system with no brain impairment based on in vivo rodent pharmacokinetic
studies and human in vitro transporter data. Proximal target engagement
and disease relevant pathway biomarkers were also favorably regulated
in an in vivo model of amyotrophic lateral sclerosis
Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis
Dual leucine zipper kinase (DLK) and leucine zipper-bearing
kinase
(LZK) are regulators of neuronal degeneration and axon growth. Therefore,
there is a considerable interest in developing DLK/LZK inhibitors
for neurodegenerative diseases. Herein, we use ligand- and structure-based
drug design approaches for identifying novel amino-pyrazine inhibitors
of DLK/LZK. DN-1289 (14), a potent and selective dual
DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life
across species and is anticipated to freely penetrate the central
nervous system with no brain impairment based on in vivo rodent pharmacokinetic
studies and human in vitro transporter data. Proximal target engagement
and disease relevant pathway biomarkers were also favorably regulated
in an in vivo model of amyotrophic lateral sclerosis
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Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.
BackgroundGenetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain.MethodsWe engineered a novel App knock-in mouse model (AppSAA) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous AppSAA mice at different ages in brain and/ or biofluids. Wild type littermate mice were used as experimental controls. We used in situ imaging technologies to define the whole-brain distribution of amyloid plaques and compare it to other AD mouse models and human brain pathology. To further explore the microglial response to AD relevant pathology, we isolated microglia with fibrillar Aβ content from the brain and performed transcriptomics and metabolomics analyses and in vivo brain imaging to measure energy metabolism and microglial response. Finally, we also characterized the mice in various behavioral assays.ResultsLeveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The AppSAA knock-in mouse model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of CSF markers of neurodegeneration. Those observations were associated with increased TSPO and FDG-PET brain signals and a hyperactivity phenotype as the animals aged.DiscussionOur findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology
Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic
GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD