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Alzheimer's disease: an update of the roles of receptors, astrocytes and primary cilia
No full textThe pathophysiological mechanisms underlying the onset and inexorable progression of the late-onset form of Alzheimer's disease (AD) are still the object of controversy. This review takes stock of some most recent advancements of this field concerning the complex roles played by the amyloid-β (Aβ)-binding p75 neurotrophin receptor (p75NTR) and calcium-sensing receptor (CaSR) and by the primary cilia in AD. Apart from their physiological roles, p75NTR is more intensely expressed in the hippocampus of human AD brains and Aβ-bound p75NTR triggers cell death, whereas Aβ-bound CaSR signalling induces the de novo synthesis and release of nitric oxide (NO), vascular endothelial growth factor (VEGF)-A and Aβ peptides (Aβs), particularly on the part of normal adult human astrocytes. The latter effect could significantly increase the pool of Aβ-and NO-producing nerve cells favouring the progressive spread of a self-sustaining and self-reinforcing 'infectious' mechanism of neural and vascular (i.e. blood-brain barrier) cell damage. Interestingly, primary cilia concentrate p75NTR receptors in their membranes and are abnormally structured/damaged in transgenic (Tg) AD-model mice, which could impact on the adult neurogenesis occurring in the dentate gyrus's subgranular zone (SGZ) that is necessary for new memory encoding, thereby favouring typical AD cognitive decline. Altogether, these findings may pave the way to novel therapeutic approaches to AD, particularly in its mild cognitive impairment (MCI) and pre-MCI stages of development
Leptin, Sonic Hedgehogs, and Neurogenesis--A Primary Cilium's Tale
Full text linkLeptin-induced signals from from Leptin receptor (R)-b stationed in the cell membrane could stimulate the primary cilium-dependent proliferation of transit amplifying cells [TANs] generated by radial glial neuronal stem cells [RG-NSCs] in the dentate gyrus of the adult hippocampal formation
What are the roles of the protein kinase Cs, particularly protein kinase C-delta, in apoptosis?
No full textPKCs are variously involved in the control of cellular functions. This review focuses on the seemingly special roles of the novel PKC-delta in apoptosis (and cell proliferation) emphasizing its endoproteolytic processing, its subcellular compartimentalization, the factors that influence it, and its behavior in response to various apoptosis-inducing agents
Increased activity of the protein kinase C-delta holoenzyme in the cytoplasmic particulate fraction precedes the activation of caspases in polyomavirus-transformed pyF111 rat fibroblasts exposed to calphostin C or topoisomerase-II inhibitors.
No full textA caspase-mediated release of the 40-kDa catalytic fragment of the delta isoform (CF-delta) of protein kinase C (PKC-delta) is involved in apoptosis, but its actual role in apoptosis development is still unknown. In an effort to understand this role, we have used polyomavirus-transformed pyF111 rat fibroblasts, which are hypersusceptible to apoptosis as they constitutively hyperexpress PKC-delta, but cannot make the antiapoptotic Bcl-2 and Bcl-X(L) proteins, while making the proapoptotic Bax protein. Calphostin C is reportedly both a specific inhibitor of PKC-delta activity (C. Keenan, N. Goode, and C. Pears, 1997, FEBS Lett. 415, 101-108) and an effective apoptogen (M. Murata et al., 1997, Cell. Mol. Life Sci. 53, 737-743). Exposure of pyF111 cells to calphostin C (75 nM) stimulated the translocation of the PKC-delta holoenzyme (holo-PKC-delta) onto the cytoplasmic particulate (CP) fraction between 15 and 45 min, which was after the release of mitochondrial cytochrome c but before the activation of cytoplasmic DEVD-specific caspases. The CF-delta fragment started accumulating only between 2 and 4 h, while apoptosis occurred mostly within 6 h. Incubating pyF111 cells with the much slower acting, apoptogenic topoisomerase-II inhibitors etoposide (VP-16) and teniposide (VM-26) also caused within 6 h a doubling of the CP-bound holo-PKC-delta-related activity but with no significant translocation of the holoenzyme to the CP fraction. Again this occurred after the release of cytochrome c but before the activation of DEVDases and the accumulation of the CF-delta. However, while calphostin C did not affect the delta-related activity in the nuclear membrane (NM) and nucleoplasmic (NP) fractions, VP-16 and VM-26 caused a prompt, large, and irreversible drop in the delta activity at the NM and a transient surge followed by a fall in the NP-associated activity. Hence, a surge of CP-anchored holo-PKC-delta activity is a common part of the signals given by various apoptogenic drugs to pyF111 cells. On the other hand, inhibition of delta-related activity, first at the NM and then in the NP fraction, is a specific feature only of the signals given by apoptogenic DNA-damaging agents
Angiogenic factor induction in and secretion by cultured phenotypically normal adult human astrocytes (NAHA) exposed to beta-amyloid peptides and proinflammatory cytokines
No full textThe induction and secretion of VEGF-A by cultured phenotypically normal adult human astrocytes (NAHAs) exposed to beta-amyloid peptides and proinflammatory cytokines is reported for the first time
Photoexcited calphostin C selectively destroys nuclear lamin B1 in neoplastic human and rat cells - A novel mechanism of action of a photodynamic tumor therapy agent
No full textLamin B1, a major component of the nuclear lamina, anchors the nucleus to the cytoskeletal cage, and controls nuclear orientation, chromosome positioning and, alongside several enzymes, fundamental nuclear functions. Exposing polyomavirus-transformed rat pyF111 fibroblasts and human cervical carcinoma (HCC) C4-I cells for 30 min to photoexcited perylenequinone calphostin C, i.e. Cal C(phiE), an established reactive oxygen species (ROS)-generator and protein kinase C (PKC) inhibitor, caused the cells to selectively oxidize and then totally destroy their nuclear lamin B1 by only 60 min after starting the treatment, i.e. when apoptotic caspases' activities had not yet increased. However, while the oxidized lamin B1 was being destroyed, lamins A/C, the lamin A-associated nuclear envelope protein emerin, and the nucleoplasmic protein cyclin E were neither oxidized nor destroyed. The oxidized lamin B was ubiquitinated and demolished in the proteasome probably by an enhanced peptidyl-glutaminase-like activity. Hence, the Cal C(phiE)-induced rapid and selective lamin B1 oxidation and proteasomal destruction ahead of the activation of apoptotic caspases was by itself a most severe molecular lesion impairing vital nuclear functions. Conversely, Cal C directly added to the cells kept in the dark damaged neither nuclear lamin B1 nor cell viability. Thus, our findings reveal a novel cell-damaging mechanism of a photodynamic tumor therapeutic agent
Is Alzheimer’s Disease at Least Partly a Ciliopathy?
Full text linkThe uninterrupted generation throughout life of the dentate gyrus [DGY] granule cells [GCs] (one site of adult neurogenesis), which initiate the encoding of novel memories, is driven by signals from the DGy GC precursors tiny, non-motile primary cilia. The hypothesis is surmised that the damage of such primary cilia be responsible of the crippling decline of memory formation in Alzheimer's Disease [AD]. Were human DGy CGs ciliated like their rodent counterparts, part of the AD cases might be indeed based upon a ciliopathy
Nuclear and cytoplasmic mechanisms of apoptosis triggered by photoactivated Calphostin C in neoplastic cells
No full textThe nuclear and cytoplasmic mechanisms of apoptosis triggered by photoactivated Calphostin C in human cervical carcinoma C4-I and rat pyF111 transformed fibroblast cells are discusse
Extracellular calcium modulates prereplicative cyclic AMP surges in EGF-stimulated primary neonatal rat hepatocytes.
No full textThe cells in nearly pure (96-98%) primary cultures of hepatocytes from neonatal rat liver in high (1.0 mM)-Ca2+, serum-free, synthetic HiWo5Ba2000 medium initiated DNA synthesis and entered mitosis between 11 and 30 h after the addition of 10 ng/ml EGF. During the 10-h prereplicative period, the cultured hepatocytes, like regenerating rat liver cells, generated two large cyclic AMP transients, one peaking between 30 min and 2 h and the other around 6 h. Hepatocytes stimulated by the same concentration of EGF in low (0.02 mM)-Ca2+ medium increased cyclic AMP synthesis as much as the EGF-treated hepatocytes in high-Ca2+ medium, but they released the additional cyclic AMP into the medium and could not generate prereplicative internal cyclic AMP surges, initiate DNA replication, or enter mitosis. These results suggest that one of the ways external Ca2+ controls prereplicative development of hepatocytes is to restrain the release of cyclic AMP and thus enable the cell to accumulate enough internal cyclic AMP to stimulate events required to initiate DNA replication
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