Changes in the thiol status of neurodegenerative disorders and the effects of copper on the amyloid beta peptide clearance

Oxidative stress is involved in the pathophysiology of certain age-associated neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Oxidative stress in these disorders is evident by the alterations in the cellular antioxidant defense system of the brain, including glutathione and antioxidant enzymes like catalase and glutathione reductase. AD is the most common disorder affecting about two thirds of cases of dementia overall and studies indicate that oxidative stress is involved in the impairment of such functions. The amyloid beta (Abeta) protein has been specified as the major source of oxidative stress in the AD brain. Association of metal ions (Cu, Fe, Zn) in Abeta induced-toxicity has been noticed recently. As a mechanistic approach, we propose that upon complex formation with Abeta copper might have an effect on Abeta clearance across the blood brain barrier. In this study, we have analyzed the thiol status in the control, AD and PD human brain tissues. Thiol levels were also determined in the brain tissues of an AD mice model. Later, we studied the effect of copper on the ability of Abeta to cross the BBB in CD-1 mice. We also measured thiol levels in RBE4 cells, an in vitro BBB model, and evaluated cell viability to test the outcome of Abeta:Cu on the BBB. Our results show that: (1) thiol status, as determined in different regions of the AD and PD brain, was altered; no change was observed in the thiol levels of SAMP8 brain regions. (2) no statistically significant differences exist in the effects of copper on the ability of Abeta to cross the BBB in vitro and in vivo. (3) there was, however, a significant difference between the brain uptake of Abeta and Abeta:Cu. We thus conclude that oxidative stress might alter the thiol status in AD and PD. In AD, copper may not have a significant effect on the clearance of Abeta.