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Post by Max on Jul 23, 2005 13:48:30 GMT -5
J Biol Chem. 2005 Jul 15; [Epub ahead of print] Related Articles, Links
Beta-amyloid-induced dynamin 1 depletion in hippocammpal neurons: A potential mechanism for early cognitive decline in Alzheimer's disease.
Kelly BL, Vassar R, Ferreira A.
Institute for Neuroscience, Northwestern University, Chicago, IL 60611.
Synaptic dysfunction is one of the earliest events in the pathogenesis of Alzheimer's disease. However, the molecular mechanisms underlying synaptic defects in AD are largely unknown. We report here that Abetathe main component of senile plaques, induced a significant decrease in dynamin 1, a protein that is essential for synaptic vesicle recycling, and hence, for memory formation and information processing. The Abetainduced dynamin 1 decrease occurred in the absence of overt synaptic loss and was also observed in the Tg2576 mouse model of Alzheimer's disease. In addition, our results provided evidence that the Abeta-induced decrease in dynamin 1 was likely the result of a calpain-mediated cleavage of dynamin 1 protein and possibly the down-regulation of dynamin 1 gene expression. These data suggest a mechanism to explain the early cognitive loss without a major decline in synapse number observed in Alzheimer's disease, and propose a novel therapeutic target for Alzheimer's disease intervention.
PMID: 16002400 [PubMed - as supplied by publisher]
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Post by Max on Jul 23, 2005 13:50:38 GMT -5
Curr Alzheimer Res. 2004 Feb;1(1):33-8. Related Articles, Links
Recent evidence regarding a role for Cdk5 dysregulation in Alzheimer's disease.
Monaco EA 3rd.
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA. monacoe@upstate.edu
Based on a growing literature, cyclin-dependent kinase 5 (Cdk5) has been implicated in the pathological processes that contribute to neurodegeneration in Alzheimer's disease (AD). Cdk5 is ubiquitously expressed, but its activity is largely localized to post-mitotic neurons due to neuron-specific expression of its activators p35 and p39. Sufficient Cdk5 activity is critical to normal central nervous system development, as in its absence, neuronal migration and axonal path finding are deranged. Conversely, excessive and mislocalized Cdk5 activity appears to be detrimental to neuronal function. In fact, the pathological hallmarks of AD, beta-amyloid aggregates and neurofibrillary tangles, have been linked to Cdk5-mediated neuronal death. In this model, beta-amyloid is the toxic stimulus that disrupts intracellular calcium homeostasis, leading to activation of calpains, a family of calcium-dependent proteases. Calpain-mediated cleavage of p35, yields a truncated p25 fragment that possesses a longer half-life, lacks the necessary sequence targeting it to membranes, but retains the capacity to activate Cdk5. The resulting excessive and mislocalized Cdk5 activity targets tau as a substrate for hyperphosphorylation, which is a prerequisite of paired helical filament (PHF) formation. A number of recent reports, utilizing diverse methods, lend further support to this model of AD neurodegeneration, and several strategies for combating Cdk5 dysregulation have even been devised. However, the study of Cdk5 in AD is not without controversy, and questions remain regarding its role in the pathology. Herein, the most recent findings regarding this model are reviewed.
PMID: 15975083 [PubMed - in process]
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Post by Max on Jul 23, 2005 13:52:36 GMT -5
Br J Pharmacol. 2005 May 23; [Epub ahead of print] Related Articles, Links
Inhibition of the cdk5/MEF2 pathway is involved in the antiapoptotic properties of calpain inhibitors in cerebellar neurons.
Verdaguer E, Alvira D, Jimenez A, Rimbau V, Camins A, Pallas M.
1Rudolf-Boehm-Institut fur Pharmakologie und Toxikologie, Universitat Leipzig, Hartelstrasse, 16-18, 04107 Leipzig, Germany.
Experimental data implicate calpain activation in the pathways involved in neuronal apoptosis. Indeed, calpain inhibitors confer neuroprotection in response to various neurotoxic stimuli. However, the pathways involved in calpain activation-induced apoptosis are not well known.We demonstrate that apoptosis (40%) induced by serum/potassium (S/K) withdrawal on cerebellar granule cells (CGNs) is inhibited by selective calpain inhibitors PD150606 (up to 15%) and PD151746 (up to 29%), but not PD145305 in CGNs. zVAD-fmk, a broad spectrum inhibitor of caspases, attenuates apoptosis (up to 20%) mediated by S/K deprivation and protects against cell death, as measured by MTT ([3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium]) assay.PD150606 and PD151746 prevented apoptosis mediated by S/K withdrawal through inhibition of calpain. Furthermore, PD151746 was able to inhibit caspase-3 activity.After S/K withdrawal, we observed an increase in cdk5/p25 formation and MEF2 phosphorylation that was prevented by 40 muM PD150606 and PD151746. This indicates that calpain inhibition may be an upstream molecular target that prevents neuronal apoptosis in vitro.Taken together, these data suggest an apoptotic route in S/K withdrawal in CGNs mediated by calpain activation, cdk5/p25 formation and MEF2 inhibition. Calpain inhibitors may attenuate S/K withdrawal-induced apoptosis and may provide a potential therapeutic target for drug treatment in a neurodegenerative process.British Journal of Pharmacology advance online publication, 23 May 2005; doi:10.1038/sj.bjp.0706280.
PMID: 15912127 [PubMed - as supplied by publisher]
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Post by Max on Jul 23, 2005 14:12:55 GMT -5
Biochem J. 1999 Oct 15;343 Pt 2:467-72. Related Articles, Links
Changes in intracellular localization of calpastatin during calpain activation.
Tullio RD, Passalacqua M, Averna M, Salamino F, Melloni E, Pontremoli S.
Department of Experimental Medicine, Biochemistry Section, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy.
Localization of the two main components of the Ca(2+)-dependent proteolytic system has been investigated in human neuroblastoma LAN-5 cells. Using a monoclonal antibody which recognizes the N-terminal calpastatin domain, it has been shown that this inhibitory protein is almost completely confined in two granule-like structures not surrounded by membranes. Similar calpastatin distribution has been found in other human and in murine cell types, indicating that aggregation of calpastatin is a general property and not an exclusive characteristic of neuronal-like cells. The existence of such calpastatin aggregates is confirmed by the kinetics of calpastatin-activity release during rat liver homogenization, which does not correspond to the rate of appearance of cytosolic proteins or to the disruption of membrane-surrounded organelles. Calpastatin distribution is affected by the intracellular increase in free Ca(2+), which results in calpastatin progressively becoming a soluble protein. However, calpain is distributed in the soluble cell fraction and, in activating conditions, partially accumulates on the plasma membrane. Similar behaviour has been observed in calpastatin localization in LAN-5 cells induced with retinoic acid, suggesting that the proteolytic system is activated during the differentiation process of these cells. The involvement of calpastatin in controlling calpain activity, rather than its activation process, and the utilization of changes in calpastatin localization as a marker of activation of the system is discussed.
PMID: 10510315 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 23, 2005 19:31:04 GMT -5
Curr Alzheimer Res. 2004 May;1(2):121-5. Related Articles, Links
The role of P-glycoprotein in cerebral amyloid angiopathy; implications for the early pathogenesis of Alzheimer's disease.
Vogelgesang S, Warzok RW, Cascorbi I, Kunert-Keil C, Schroeder E, Kroemer HK, Siegmund W, Walker LC, Pahnke J.
Department of Neuropathology, University of Greifswald, Germany.
It has been shown in vitro that beta-amyloid (Abeta) is transported by P-glycoprotein (P-gp). Previously, we demonstrated that Abeta immunoreactivity is significantly elevated in brain tissue of individuals with low expression of P-gp in vascular endothelial cells. These findings led us to hypothesize that P-gp might be involved in the clearance of Abeta in normal aging and particularly in Alzheimer's disease (AD). As we were interested in the early pathogenesis of Abeta deposition, we studied the correlation between cerebral amyloid angiopathy (CAA) and P-gp expression in brain tissue samples from 243 non-demented elderly cases (aged 50 to 91 years). We found that endothelial P-gp and vascular Abeta were never colocalized, i.e., vessels with high P-gp expression showed no Abeta deposition in their walls, and vice versa. Abeta deposition occurred first in arterioles where P-gp expression was primarily low, and disappeared completely with the accumulation of Abeta. At this early stage, P-gp was upregulated in capillaries, suggesting a compensatory mechanism to increase Abeta clearance from the brain. Capillaries were usually affected only at later stages of CAA, at which point P-gp was lost even in these vessels. We hypothesize that Abeta clearance may be altered in individuals with diminished P-gp expression due, e.g., to genetic or environmental effects (such as drug administration). The impairment of Abeta clearance could lead to the accumulation and earlier deposition of Abeta, both in the walls of blood vessels and in the brain parenchyma, thus elevating the risk of CAA and AD.
PMID: 15975076 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 23, 2005 20:08:00 GMT -5
Trends Endocrinol Metab. 2005 Mar;16(2):59-65. Related Articles, Links
The role of insulin receptor signaling in the brain.
Plum L, Schubert M, Bruning JC.
Institute for Genetics and Center for Molecular Medicine Cologne, Department of Mouse Genetics and Metabolism, University of Cologne, Weyertal 121, 50931 Cologne, Germany.
The insulin receptor (IR) is expressed in various regions of the developing and adult brain, and its functions have become the focus of recent research. Insulin enters the central nervous system (CNS) through the blood-brain barrier by receptor-mediated transport to regulate food intake, sympathetic activity and peripheral insulin action through the inhibition of hepatic gluconeogenesis and reproductive endocrinology. On a molecular level, some of the effects of insulin converge with those of the leptin signaling machinery at the point of activation of phosphatidylinositol 3-kinase (PI3K), resulting in the regulation of ATP-dependent potassium channels. Furthermore, insulin inhibits neuronal apoptosis via activation of protein kinase B in vitro, and it regulates phosphorylation of tau, metabolism of the amyloid precursor protein and clearance of beta-amyloid from the brain in vivo. These findings indicate that neuronal IR signaling has a direct role in the link between energy homeostasis, reproduction and the development of neurodegenerative diseases.
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Post by Max on Jul 27, 2005 7:03:04 GMT -5
Neuroscience. 2001;105(3):651-61. Related Articles, Links
Regulation of apolipoprotein E secretion in rat primary hippocampal astrocyte cultures.
Cedazo-Minguez A, Hamker U, Meske V, Veh RW, Hellweg R, Jacobi C, Albert F, Cowburn RF, Ohm TG.
Karolinska Institutet, NEUROTEC, Section for Experimental Genetics, Huddinge, Sweden.
Apolipoprotein E isoforms may have differential effects on a number of pathological processes underlying Alzheimer's disease. Recent studies suggest that the amount, rather than the type, of apolipoprotein E may also be an important determinant for Alzheimer's disease. Therefore, understanding the regulated synthesis of apolipoprotein E is important for determining its role in Alzheimer's disease.We show here that in rat primary hippocampal astrocyte cultures, dibutyryl-cAMP increased apolipoprotein E secretion with time in a dose-dependent manner (to 177% at 48 h) and that retinoic acid potentiated this effect (to 298% at 48 h). Dibutyryl-cAMP also gave a rapid, albeit transient, increase of apolipoprotein E mRNA expression (to 200% at 1 h). In contrast, the protein kinase C activator phorbol 12-myristate 13-acetate decreased both apolipoprotein E secretion (to 59% at 48 h) and mRNA expression (to 22% at 1 h). Phorbol 12-myristate 13-acetate also reversed the effects of dibutyryl-cAMP. Apolipoprotein E secretion was also modulated by receptor agonists for the adenylyl cyclase/cAMP pathway. Isoproterenol (50 nM, a beta-adrenoceptor agonist) enhanced, while clonidine (250 nM, an alpha2-adrenoceptor agonist) decreased, secreted apolipoprotein E. We also analysed the effects of agonists for the phospholipase C/protein kinase C pathway. Arterenol (1 microM, an alpha1-adrenoceptor agonist) and serotonin (2.5 microM) enhanced, whereas carbachol (10 microM, an acetylcholine muscarinic receptor agonist) decreased secreted apolipoprotein E. The effects of these non-selective receptor agonists were modest, probably due to effects on different signalling pathways. Arterenol also potentiated the isoproterenol-mediated increase. We also show that phorbol 12-myristate 13-acetate and dibutyryl-cAMP have opposite effects on nerve growth factor, as compared to apolipoprotein E, secretion, suggesting that the results obtained were unlikely to be due to a general effect on protein synthesis.We conclude that astrocyte apolipoprotein E production can be regulated by factors that affect cAMP intracellular concentration or activate protein kinase C. Alterations in these signalling pathways in Alzheimer's disease brain may have consequences for apolipoprotein E secretion in this disorder.
PMID: 11516830 [PubMed - indexed for MEDLINE]
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Post by Max on Oct 4, 2005 4:10:26 GMT -5
J Neurochem. 2005 Aug;94(3):828-38. Related Articles, Links
Age-associated changes in mRNA levels of Phox2, norepinephrine transporter and dopamine beta-hydroxylase in the locus coeruleus and adrenal glands of rats.
Zhu MY, Wang WP, Iyo AH, Ordway GA, Kim KS.
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA. mzhu@psychiatry.umsmed.ed
Age-related changes in the gene expression of the transcription factors, Phox2a and 2b, and two marker proteins, norepinephrine transporter (NET) and dopamine beta-hydroxylase (DBH), of noradrenergic neurons were characterized in the locus coeruleus (LC) and adrenal glands using in situ hybridization. Analysis of changes was performed in rats that were 1-23 months of age. Compared to 1-month-old rats, there was a 62% increase of Phox2a messenger RNA (mRNA) in the LC of 3-month-old rats, and a decline of 37% in 23-month-old rats. In contrast, levels of Phox2b mRNA in the LC remained unchanged in 3-month-old rats, but declined to a 30% reduction in 23-month-old rats. Interestingly, mRNA levels of NET in the LC decreased with increasing age to a reduction of 29%, 30% and 43% in 3-, 8- and 23-month-old rats, respectively. Similarly, DBH mRNA in the LC declined with increasing age to a 56% reduction in 23-month-old rats. mRNA levels of Phox2a, Phox2b, NET and DBH in the adrenal medulla of 23-month-old rats were significantly lower than those of 1-month-old rats. Semi-quantitative reverse transcription assays of the same genes yielded data similar to in situ hybridization experiments, with beta-actin mRNA levels being unchanged across the ages. Taken together, these data reveal that reduced Phox2 mRNAs in the LC and adrenal medulla of aging rats are accompanied by a coincidental decline in mRNA levels of NET and DBH and suggest a possible relationship between Phox2 genes and the marker genes in noradrenergic neurons after birth.
PMID: 16033425 [PubMed - indexed for MEDLINE]
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