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VITAGENES, METABOLIC STRESS AND HORMESIS IN AGING AND NEURODEGENERATIVE DISORDERS Vittorio Calabrese Chairman and Professor of Clinical Biochemistry, Faculty of Medicine, University of Catania, Italy; Protein quality control is a critical feature of intracellular homeostasis. In particular, unfolded or misfolded proteins resulting from environmental stresses or free radicals are rapidly degraded via the ubiquitin–proteasome pathway 1 . In addition, modulation of endogenous cellular defense mechanisms via the stress response signaling represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as neurodegeneration and cancer 1 . Protein thiols play a key role in redox sensing, and regulation of cellular redox state is crucial mediator of multiple metabolic, signalling and transcriptional processes. Under optimal conditions long-term health protection is accomplished by protein homeostasis, a highly complex network of molecular interactions that balances protein biosynthesis, folding, translocation, assembly/disassembly, and clearance 2,3 . Efficient functioning of maintenance and repair processes is crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes 4-8 . The term vitagenes refers to a group of genes which are strictly involved in preserving cellular homeostasis during stressful conditions. The vitagene family is actually composed of the heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin system and the sirtuin system 9 . Dietary antioxidants, such as polyphenols and L-carnitine/acetyl-L-carnitine, have recently been demonstrated in vitro to be neuroprotective through the activation of hormetic pathways, including vitagenes 10-12 . Over the past decade there has been a remarkable increase of interest in hormesis as a result of more significance being given to low dose effects and the use of more powerful study designs which have enabled to identify rational approaches to detect hormetic biphasic dose responses in the low dose zone. The hormetic dose–response, challenging long-standing beliefs about the nature of the dose–response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases, including oxidant disorders. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. We have recently focused our research on the role of acetylcarnitine in the defense mechanisms against cellular stress and neurodegeneration. In addition, with a redox proteomics approach, we identified mitochondrial oxidatively modified proteins as a function of brain aging, specifically in those brain regions, such as cortex and hippocampus, that are commonly affected by the aging process. In all brain regions examined, many of the identified proteins were energy-related, such as pyruvate kinase, ATP synthase, aldolase, creatine kinase, and a-enolase. These alterations were associated with increased expression of Hsps, as well as carnosinase and thioredoxin reductase and with significant changes in both cytosolic and mitochondrial redox status in all brain regions analyzed. This findings are relevant to potential pharmacological interventions in healthy medicine strategy, pointing to maximize cellular stress resistance of the brain thus providing neuroprotection 9-14 , and will be extended to other systemic oxidant disorders such as diabetic nephropathy or cancer. References: 1 Halliwell B. (2008) Arch Bioch Biophys 476:107; 2 Calabrese V. (2007) Nature Neurosci 8,766; 3 Gutteridge JM (2010) BBRC 393:561; 4 Calabrese V. (2010) J Neurosi Res 88:3498; 5 Calabrese V. (2010) Antiox Redox Signal 13:1763; 6 Calabrese V. (2009) Front Biosci. 14:376; 7 Calabrese V. (2009) Antiox Redox Signal 11:2717; 8 Calabrese V. (2010) Neurochem Res 35:1880; 9 Calabrese V. (2009) Antiox Redox Signal 11:2759; 10 Calabrese EJ (2010) Hum Exp Toxicol. 29:1034; 11 Calabrese EJ (2010) Hum Exp Toxicol. 29:980; 12 Calabrese V. (2010) Neurochem Res 35:2184; 13 Mattson MP. (2010) Neuron 67:900; 14 Min SW. (2010) Neuron 67:953. 58
p75NTR regulates A! deposition by increasing A! production but inhibiting A! aggregation with its extracellular domain Xin-Fu Zhou, Xin Wang, Jian-Jun Lu, Qiao-Xin Li, Chang-Yue Gao, Xiao-Hong Liu, Yin Sun, Miao Yang, Yoon Lim, Genevieve Evin, Jin-Hua Zhong, Hua-Dong Zhou, Yan- Jiang Wang Department of Human Physiology and Centre for Neuroscience, Flinders University GPO Box 2100, Adelaide, South Australia Accumulation of toxic amyloid-beta (A!) in the cerebral cortex and hippocampus is a major pathological feature of Alzheimer’s disease (AD). The neurotrophin receptor, p75NTR, has been proposed to mediate A!- induced neurotoxicity; however its role in the development of AD remains to be clarified. The p75NTR/ExonIII-/- mice and APPSwe/PS1dE9 mice were crossed to generate transgenic AD mice with deletion of p75NTR gene. Study of p75NTR immunoreactivity in the AD model APPSwe/PS1dE9 transgenic mice, indicates its localization to the basal forebrain neurons and degenerative neurites in amyloid plaques of neocortex, increase with aging, and further activation by A! accumulation. Deletion of the p75NTR gene by crossing APPSwe/PS1dE9 mice with p75NTR knockout mice reduced soluble A! levels in the brain and plasma, but increased the accumulation of insoluble A! and A! plaque formation. There was no change in the levels of amyloid precursor protein (APP) and its proteolytic derivatives, or ", ! and # secretase activities, or in levels of BACE1, neprilysin (NEP) and insulin degrading enzyme (IDE) proteins. Recombinant extracellular domain of p75NTR attenuated the oligomerization and fibrillation of synthetic A!42 peptide in vitro, and reduced local A! plaques after hippocampus injection in vivo. In addition, deletion of p75NTR attenuated microgliosis but increased the microhemorrhage profiles in the brain. The deletion of p75NTR did not significantly change the cognitive function of the mice up to the age of 9 months. Our data suggest that p75NTR plays a critical role in regulating A! levels by both increasing A! production and attenuating its aggregation and they caution that a therapeutic intervention simply reducing p75NTR may exacerbate AD pathology. 59
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Luxembourg, January 26th to 28th, 2
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Luxembourg, January 26th to 28th, 2
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Preface In 1998, we organized the f
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European Research Institute for Int
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Page 16 and 17: Many thanks to all exhibitors Pleas
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Page 29 and 30: Towards understanding of life and d
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Session 6: Epigenetics Poster 6 Fun
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Session 8: Gene expression networks
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Session 9: Neurodegenerative Diseas
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List of participants (In alphabetic
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Mrs. Emilie Bana Laboratoire d'Ing
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Dr. Alessandro Corsaro Laboratory o
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Pr. Paul Fisher Microbial Cell Biol
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Mr. Kasper Hoebe Cincinnati Childre
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Mr. Hendrik Koopmans Cell Biology W
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Mr. Romuald Menth Technical Support
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