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Increased Cu efflux from the nerve cell followed by reduced SOD-1 enzyme activity (a copper/zinc antioxidant enzyme) results in increased oxidative stress and neuronal loss.

Purdey, Brown, Wong and others on this path for years are finally seeing an influx of scientists on their side.

Clin Neuropathol. 2006 Jul-Aug;25(4):163-71

A vicious circle: role of oxidative stress, intraneuronal Abeta and Cu in Alzheimer's disease.

Bayer TA, Schafer S, Breyhan H, Wirths O, Treiber C, Multhaup G.
Department of Neurobiology, Clinic of Psychiatry, University of the Saarland, Homburg, Germany. [email protected]

Recent evidence indicates that both intraneuronal Abeta and Cu are involved in the pathological processes in Alzheimer's disease (AD). This perspective shows a possible interrelation of these factors. AbetaPP, the precursor of Abeta which represents the main constituent of amyloid plaques, is involved in Cu homeostasis in mammals. In vitro observations and in vivo data obtained from AbetaPP mouse models provide strong evidence that AbetaPP and the resulting Abeta overproduction facilitate intracellular Cu to leave the cell. An increased Cu efflux seems to lead to Cu deficiency and, subsequently, reduced SOD-1 activity. The Cu-dependent SOD-1 activity is the main enzyme involved in detoxifying free radicals. Several reports have shown that oxidative stress is an invariable age-dependent feature in the brain of AD patients. Increased oxidative stress leads to an increase in intraneuronal Abeta accumulation, which has been shown to be the main trigger for neuronal loss in transgenic mouse models. Thus, we conclude that bioavailability of Cu is a crucial point for the pathogenesis of AD.

PMID: 16866297


Exp Eye Res. 2006 Sep 2
The prion protein is neuroprotective against retinal degeneration in vivo.

Frigg R, Wenzel A, Samardzija M, Oesch B, Wariwoda H, Navarini AA, Seeliger MW, Tanimoto N, Reme C, Grimm C.

Lab for Retinal Cell Biology, Department of Ophthalmology, Center for Integrative Human Physiology (CIHP) and Neuroscience Center (ZNZ), University of Zurich, Frauenklinikstrasse 24, 8091 Zurich, Switzerland.

A common feature of neurodegenerative disorders is acute or progressive loss of neurons due to apoptosis. The pathological isoform of the prion protein is associated with retinal apoptosis and the cellular isoform (PrP(c)) has been shown to mediate protection from apoptosis in cell culture and in neonatal retinal explants. Using a model of light-induced photoreceptor apoptosis, we show in vivo that the levels of PrP(c) expression in the retina inversely correlate with the susceptibility of photoreceptors to light damage. Dissection of apoptotic signalling cascades suggests that PrP(c) acts neuroprotectively downstream of AP-1 induction. Our results reveal PrP as a neuroprotective/anti-apoptotic factor in vivo and suggest that PrP(c) may function as a guardian of neuronal integrity.

PMID: 16952355


Biochem Biophys Res Commun. 2006 Aug 28;
Dividing roles of prion protein in staurosporine-mediated apoptosis.

Zhang Y, Qin K, Wang J, Hung T, Zhao RY.

Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, People's Republic of China; Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 100052, People's Republic of China.

Prion protein (PrP(C)) is a normal cellular glycoprotein that is expressed in almost all tissues including the central nervous system. Much attention has been focused on this protein because conversion of the normal PrP(C) to the diseased form (PrP(Sc)) plays an essential role in transmissible spongiform encephalopathies such as mad cow disease and Creutzfeldt-Jakob disease. In spite of the extensive effort, the normal physiological function of PrP(C) remains elusive. Emerging evidence suggests that PrP(C) plays a protective role against cellular stresses including apoptosis induced by various pro-apoptotic agents such as Bax and staurosporine (STS), however, other reports showed overexpression of PrP(C) enhances STS-mediated apoptosis. In this study, we took a different approach by depleting endogenous PrP(C) using specific interfering RNA technique and compared the depleting and overproducing effects of PrP(C) on STS-induced apoptosis in neuro-2a (N2a) cells. We demonstrate here that down-regulation of PrP(C) sensitizes N2a cells to STS-induced cytotoxicity and apoptosis. The enhanced apoptosis induced by STS was shown by increased DNA fragmentation, immunoreactivity of Bax, and caspase-3 cleavage. We also showed that overproduction of PrP(C) had little or no effect on STS-mediated DNA fragmentation in N2a cells but it augments STS-mediated apoptosis in HEK293 cells, suggesting a cell line-specific effect. In addition, the inhibitory effect of PrP(C) on STS-mediated cellular stress appears to be modulated in part through induction of cell cycle G2 accumulation. Together, our data suggest that physiological level of endogenous PrP(C) plays a protective role against STS-mediated cellular stress. Loss of this protection could render cells more prone to cellular insults such as STS.

PMID: 16950206

function of the healthy prion protein has not been elusive should researchers choose to read papers such as Purdeys and DR Browns, BS Wongs - now everyone wants the glory.
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