Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling ...networks regulated by the p75 neurotrophin receptor (p75
) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75
will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75
signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75
signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.
Abstract
The structural defects in two-dimensional transition metal dichalcogenides, including point defects, dislocations and grain boundaries, are scarcely considered regarding their potential to ...manipulate the electrical and optical properties of this class of materials, notwithstanding the significant advances already made. Indeed, impurities and vacancies may influence the exciton population, create disorder-induced localization, as well as modify the electrical behaviour of the material. Here we report on the experimental evidence, confirmed by
ab initio
calculations, that sulfur vacancies give rise to a novel near-infrared emission peak around 0.75 eV in exfoliated MoS
2
flakes. In addition, we demonstrate an excess of sulfur vacancies at the flake’s edges by means of cathodoluminescence mapping, aberration-corrected transmission electron microscopy imaging and electron energy loss analyses. Moreover, we show that ripplocations, extended line defects peculiar to this material, broaden and redshift the MoS
2
indirect bandgap emission.
The current review summarizes the pathobiology of nerve growth factor (NGF) and its cognate receptors during the progression of Alzheimer's disease (AD). Both transcript and protein data indicate ...that cholinotrophic neuronal dysfunction is related to an imbalance between TrkA-mediated survival signaling and the NGF precursor (proNGF)/p75
-mediated pro-apoptotic signaling, which may be related to alteration in the metabolism of NGF. Data indicate a spatiotemporal pattern of degeneration related to the evolution of tau pathology within cholinotrophic neuronal subgroups located within the nucleus basalis of Meynert (nbM). Despite these degenerative events the cholinotrophic system is capable of cellular resilience and/or plasticity during the prodromal and later stages of the disease. In addition to neurotrophin dysfunction, studies indicate alterations in epigenetically regulated proteins occur within cholinotrophic nbM neurons during the progression of AD, suggesting a mechanism that may underlie changes in transcript expression. Findings that increased cerebrospinal fluid levels of proNGF mark the onset of MCI and the transition to AD suggests that this proneurotrophin is a potential disease biomarker. Novel therapeutics to treat NGF dysfunction include NGF gene therapy and the development of small molecule agonists for the cognate prosurvival NGF receptor TrkA and antagonists against the pan-neurotrophin p75
death receptor for the treatment of AD.
The High Altitude Water Cherenkov (HAWC) gamma-ray observatory is a wide field of view observatory sensitive to 500 GeV-100 TeV gamma-rays and cosmic rays. It can also perform diverse indirect ...searches for dark matter annihilation and decay. Among the most promising targets for the indirect detection of dark matter are dwarf spheroidal galaxies. These objects are expected to have few astrophysical sources of gamma-rays but high dark matter content, making them ideal candidates for an indirect dark matter detection with gamma-rays. Here we present individual limits on the annihilation cross section and decay lifetime for 15 dwarf spheroidal galaxies within the field of view, as well as their combined limit. These are the first limits on the annihilation cross section and decay lifetime using data collected with HAWC. We also present the HAWC flux upper limits of the 15 dwarf spheroidal galaxies in half-decade energy bins.
Following stroke, the damaged tissue undergoes liquefactive necrosis, a stage of infarct resolution that lasts for months although the exact length of time is currently unknown. One method of repair ...involves reactive astrocytes and microglia forming a glial scar to compartmentalize the area of liquefactive necrosis from the rest of the brain. The formation of the glial scar is a critical component of the healing response to stroke, as well as other central nervous system (CNS) injuries. The goal of this study was to evaluate the toxicity of the extracellular fluid present in areas of liquefactive necrosis and determine how effectively it is segregated from the remainder of the brain. To accomplish this goal, we used a mouse model of stroke in conjunction with an extracellular fluid toxicity assay, fluorescent and electron microscopy, immunostaining, tracer injections into the infarct, and multiplex immunoassays. We confirmed that the extracellular fluid present in areas of liquefactive necrosis following stroke is toxic to primary cortical and hippocampal neurons for at least 7 weeks following stroke, and discovered that although glial scars are robust physical and endocytic barriers, they are nevertheless permeable. We found that molecules present in the area of liquefactive necrosis can leak across the glial scar and are removed by a combination of paravascular clearance and microglial endocytosis in the adjacent tissue. Despite these mechanisms, there is delayed atrophy, cytotoxic edema, and neuron loss in regions adjacent to the infarct for weeks following stroke. These findings suggest that one mechanism of neurodegeneration following stroke is the failure of glial scars to impermeably segregate areas of liquefactive necrosis from surviving brain tissue.
•Liquefactive necrosis lasts for weeks following stroke.•The extracellular fluid in areas of liquefactive necrosis is neurotoxic.•Glial scars are permeable to the extracellular fluid present in areas of liquefactive necrosis.•There is progressive neurodegeneration around areas of liquefactive necrosis after stroke.
The ability to differentiate one's body from others is a fundamental aspect of social perception and has been shown to involve the integration of sense modalities attributable to the self. Though ...behavioral studies in infancy have investigated infants' discrimination of body-related multisensory stimuli, whether they attribute this information as belonging to the self is still unknown. In human adults, neuroimaging studies have demonstrated the recruitment of a specific set of brain regions in response to body-related multisensory integration. To test whether the infant brain integrates this information similarly to adults, in a first functional near-infrared spectroscopy study we investigated the role of visual-proprioceptive feedback when temporal cues are manipulated by showing 5-month-old infants an online video of their own face while the infant was performing movements. To explore the role of body-related contingency further, in a second study we investigated whether cortical activation in response to self-initiated movements and external tactile stimulation was similar to that found in the first study. Our results indicate that infants' specialized cortical activation in response to body-related contingencies is similar to brain activation seen in response to body awareness in adults.
Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, ...cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients and Mecp2-null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.
MR imaging tractography is increasingly used to perform noninvasive presurgical planning for brain gliomas. Recently, constrained spherical deconvolution tractography was shown to overcome several ...limitations of commonly used DTI tractography. The purpose of our study was to evaluate WM tract alterations of both the corticospinal tract and arcuate fasciculus in patients with high-grade gliomas, through qualitative and quantitative analysis of probabilistic constrained spherical deconvolution tractography, to perform reliable presurgical planning.
Twenty patients with frontoparietal high-grade gliomas were recruited and evaluated by using a 3T MR imaging scanner with both morphologic and diffusion sequences (60 diffusion directions). We performed probabilistic constrained spherical deconvolution tractography and tract quantification following diffusion tensor parameters: fractional anisotropy; mean diffusivity; linear, planar, and spherical coefficients.
In all patients, we obtained tractographic reconstructions of the medial and lateral portions of the corticospinal tract and arcuate fasciculus, both on the glioma-affected and nonaffected sides of the brain. The affected lateral corticospinal tract and the arcuate fasciculus showed decreased fractional anisotropy (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) and linear coefficient (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) along with increased spherical coefficient (z = -2.51, n = 20, P = .006; z = -2.52, n = 20, P = .006). Mean diffusivity values were increased only in the lateral corticospinal tract (z = -2.53, n = 20, P = .006).
In this study, we demonstrated that probabilistic constrained spherical deconvolution can provide essential qualitative and quantitative information in presurgical planning, which was not otherwise achievable with DTI. These findings can have important implications for the surgical approach and postoperative outcome in patients with glioma.
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