131 research outputs found
A paradigm-changing surprise from dentate gyrus granule cells- cilium-localized p75NTR may drive their progenitor cell proliferation
No full textPeer reviewed: YesNRC publication: Ye
The Possible Roles of the Dentate Granule Cell’s Leptin and Other Ciliary Receptors in Alzheimer’s Neuropathology
No full textDentate-gyral granule cells in the hippocampus plus dentate gyrus memory-recording/retrieving machine, unlike most other neurons in the brain, are continuously being generated in the adult brain with the important task of separating overlapping patterns of data streaming in from the outside world via the entorhinal cortex. This “adult neurogenesis” is driven by tools in the mature granule cell’s cilium. Here we report our discovery of leptin’s LepRb receptor in this cilium. In addition, we discuss how ciliary LepRb signaling might be involved with ciliary p75NTR and SSTR3 receptors in adult neurogenesis and memory formation as well as attenuation of Alzheimer’s neuropathology by reducing the production of its toxic amyloid-β-derived drivers
PLA(2) signaling is involved in calpain-mediated degradation of synaptic dihydropyrimidinase-like 3 protein in response to NMDA excitotoxicity
No full textDihydropyrimidinase-like 3 (DPYSL3) is believed to play a role in neuronal differentiation, axonal outgrowth and neuronal regeneration, as well as cytoskeleton organization. Recently we have shown that glutamate excitotoxicity and oxidative stress result in calpain-dependent cleavage of DPYSL3, and that NOS plays a role in this process [R. Kowara, Q. Chen, M. Milliken, B. Chakravarthy, Calpain-mediated truncation of dihydropyrimidinase-like 3 protein (DPYSL3) in response to NMDA and H2O2 toxicity, J. Neurochem. 95 (2005) 466-474; R. Kowara, K.L. Moraleja, B. Chakravarthy, Involvement of nitric oxide synthase and ROS-mediated activation of L-type voltage-gated Ca(2+) channels in NMDA-induced DPYSL3 degradation, Brain Res. 1119 (2006) 40-49]. The present study investigates the involvement of PLA(2) signaling in NMDA-induced DPYSL3 degradation. Exposure of rat primary cortical neurons (PCN) to PLA(2) and COX-2 inhibitors significantly prevented NMDA-induced DPYSL3 degradation. Since the metabolic product of PLA(2) signaling, PGE(2), which augments toxic effect of NMDA, is known to stimulate cAMP, the effect of adenyl cyclase activator (forskolin plus IBMX) and inhibitor (MDL12,300) on NMDA-induced DPYSL3 degradation was tested. Our data indicate that the activation of adenyl cyclase contributes to NMDA-induced DPYSL3 degradation. Furthermore, cAMP-dependent protein kinase (PKA) inhibitor PKI (14-22) provided additional evidence of PKA involvement in NMDA-induced DPYSL3 degradation. In summary, the obtained data show the contribution of PLA(2) signaling to NMDA-induced calpain activation and subsequent degradation of synaptic protein DPYSL3NRC publication: Ye
Preventing the spread of Alzheimer's disease neuropathology: a role for calcilytics?
No full textThe "amyloid cascade hypothesis" posits that an extracellular build-up of amyloid-\u3b2 oligomers (A\u3b2-os) and polymers (fibrils) subsequently inducing toxic hyperphosphorylated (p)-Tau oligomers (p-Tau-os) and neurofibrillary tangles starts the sporadic late-onset Alzheimer's disease (LOAD) in the aged lateral entorhinal cortex. Conversely, mutated genes cause a diffuse cerebral A\u3b2s/A\u3b2-os overproduction promoting early-onset familiar AD (EOFAD). Surplus exogenous A\u3b2-os exert toxic actions at several levels. They reach the nuclei of human astrocyte-neurons teams (ANTs) to enhance the transcription of A\u3b2 precursor protein (APP) and \u3b2-secretase/BACE1 genes. The overexpressed APP and BACE1 proteins act in concert with \u3b3-secretase to overproduce endogenous A\u3b2s/A\u3b2-os, of which a few enter the nuclei to upkeep A\u3b2s overproduction, while the rest gather in the cytoplasm, damage mitochondria, and are oversecreted. Simultaneously, extracellular A\u3b2-os bind the ANTs' calcium-sensing receptors (CaSRs) activating signalings that hinder the proteolysis and hence favor the surplus hoarding/secretion of A\u3b2s/A\u3b2-os. Overreleased A\u3b2-os spread, reach growing numbers of adjacent ANTs to recruit them to overproduce/oversecrete further A\u3b2-os amounts via the just mentioned mechanisms. Alongside, A\u3b2\u2022CaSR signalings elicit a noxious overproduction/overrelease of nitric oxide (NO) and vascular endothelial growth factor (VEGF)-A from ANTs' astrocytes. While astrocytes survive the toxic onslaught, neurons die. Thus, AD progression is driven by ceaselessly self-sustaining neurotoxic cycles, which engender first A\u3b2-os and later p-Tau-os that cooperatively destroy increasingly wider cognition-related cortical areas. Notably, a highly selective allosteric CaSR antagonist (calcilytic), like NPS 2143, does preserve human cortical postnatal HCN-1A neurons viability notwithstanding the presence of exogenous A\u3b2-os by suppressing the otherwise elicited oversecretion and spread of newly synthesized A\u3b2-os. Therefore, if given at minimal cognitive impairment or earlier stages, calcilytics could halt AD progression and preserve the patients' cortical neurons, cognitive abilities, and eventually life.Peer reviewed: YesNRC publication: Ye
sj-pdf-1-jcb-10.1177_0271678X211035625 - Supplemental material for Preclinical <i>in vivo</i> longitudinal assessment of KG207-M as a disease-modifying Alzheimer’s disease therapeutic
No full textSupplemental material, sj-pdf-1-jcb-10.1177_0271678X211035625 for Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer’s disease therapeutic by Min Su Kang, Monica Shin, Julie Ottoy, Arturo Aliaga Aliaga, Sulantha Mathotaarachchi, Kely Quispialaya, Tharick A Pascoal, D Louis Collins, M. Mallar Chakravarty, Axel Mathieu, Åsa Sandelius, Kaj Blennow, Henrik Zetterberg, Gassan Massarweh, Jean-Paul Soucy, A Claudio Cuello, Serge Gauthier, Michael Waterston, Nathan Yoganathan, Etienne Lessard, Arsalan Haqqani, Kerry Rennie, Danica Stanimirovic, Balu Chakravarthy and Pedro Rosa-Neto in Journal of Cerebral Blood Flow & Metabolism</p
P1‐345: The shortening of somatostatin receptor‐3‐bearing primary cilia of neurons in the dentate gyri of Aβ <sub>1‐42</sub> and P301L‐tau accumulating transgenic Alzheimer‐mice but not in mice accumulating only Aβ <sub>1‐42</sub>
No full textAmyloid-β25-35, an Amyloid-β1-42 Surrogate, and Proinflammatory Cytokines Stimulate VEGF-A Secretion by Cultured, Early Passage, Normoxic Adult Human Cerebral Astrocytes
No full textCerebrovascular angiopathy affects late-onset Alzheimer's disease (LOAD) brains by possibly increasing vascular endothelial growth factor (VEGF). A expression, thereby stimulating endothelial cell proliferation and migration. Indeed, VEGF-A gene upregulation, with increased VEGF-A protein content of reactive astrocytes and microglia, occurs in LOAD brains, and neovascularization was observed one week after injecting amyloid-β (Aβ)1-42 into rat hippocampus. We have now found, with cultured 'normoxic' normal adult human astrocytes (NAHAs), that fibrillar Aβ25-35 (an active Aβ1-42 fragment) or a cytokine mixture (the (CM)-trio (interleukin [IL]-1β+interferon [IFN]-γ+tumor necrosis factor [TNF]-α), or pair (IFN-γ+TNF-α) like those produced in LOAD brains) stimulates the nuclear translocation of stabilized hypoxia-inducible factor (HIF)-1α protein and its binding to VEGF-A hypoxia-response elements; the mRNA synthesis for three VEGF-A splice variants (121, 165, 189); and the secretion of VEGF-A165. The CM-trio was the most powerful stimulus, IFN-γ+TNF-α was less potent, and other cytokine pairs or single cytokines or Aβ35-25 were ineffective. While Aβ25-35 did not change HIF-1β protein levels, the CM-trio increased both HIF-1α and HIF-1β protein levels, thereby giving an earlier and stronger stimulus to VEGF-A secretion by NAHAs. Thus, increased VEGF-A secretion from astrocytes stimulated by Aβ1-42 and by microglia-released cytokines might restore angiogenesis and Aβ1-42 vascular clearance
Identification of protein kinase C inhibitory activity associated with a polypeptide isolated from a phage display system with homology to PCM-1, the pericentriolar material-1 protein
No full textWe had previously identified a protein kinase C (PKC) inhibitor in murine neuroblastoma cells (Chakravarthy et al. [1]). Similar PKC inhibitory activity was also found in adult rat brain. Using polyclonal antibodies raised against the partially purified PKC inhibitor from rat brain as bait, we isolated a putative brain PKC inhibitor using a T-7 phage display system expressing human brain cDNA library. After enriching the phage population expressing the putative PKC inhibitor with four rounds of biopanning using ELISA and in vitro PKC binding assays, we identified a phage clone that expressed a product with significant PKC inhibitory activity. We have cloned and expressed this cDNA in a bacterial system and purified the recombinant protein. This polypeptide (174 amino acids) is highly homologous to a region of the 228-kDa PCM-1, the human pericentriolar material 1 protein. We have mapped this polypeptide\u2019s PKC-inhibitory domain and shown its PKC inhibitory activity in vitro. However, it will need to be determined whether the full-length PCM-1 protein possesses PKC inhibitory activity in vivo, and if so, how this might contribute to PCM-1\u2019s recently demonstrated roles in ciliogenesis and neurogenesis.Peer reviewed: YesNRC publication: Ye
Reymont na Balu Prasy
No full textThe article discusses an unpublished short manuscript by Władysław Stanisław Reymont. A note placed by the author of The Peasants on a ball ticket from 1922 constitutes a starting point for the reconstruction of a minor, although particularly interesting, episode from the late period in the artist’s life
In situ electron microscopy study of structural transformations in 2D CoSe<sub>2</sub>
No full textThermally induced structural transformation of 2D materials opens unique avenues for generating other 2D materials by physical methods. Imaging these transitions in real time provides insight into synthesis routes and property tuning. We have used in situ transmission electron microscopy (TEM) to follow thermally induced structural transformations in layered CoSe2. Three transformation processes are observed: orthorhombic to cubic-CoSe2, cubic-CoSe2 to hexagonal-CoSe, and hexagonal to tetragonal-CoSe. In particular, the unit-cell-thick orthorhombic structure of CoSe2 transforms into cubic-CoSe2 via rearrangement of lattice atoms. Cubic-CoSe2 transforms to hexagonal-CoSe at elevated temperatures through the removal of chalcogen atoms. All nanosheets transform to basal-plane-oriented hexagonal 2D CoSe. Finally, the hexagonal to tetragonal transformation in CoSe is a rapid process wherein the layered morphology of hexagonal-CoSe is broken and islands of tetragonal-CoSe are formed. Our results provide nanoscopic insights into the transformation processes of 2D CoSe2 which can be used to generate these intriguing 2D materials and to tune their properties by modifying their structures for electro-catalytic and electronic applications.Engineering Thermodynamic
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