CNS cholesterol metabolism is associated with soluble amyloid precursor protein production in Alzheimer's disease

Abstract

induced by Abeta. There is compelling evidence that Cu and Zn bind directly to Abeta in AD. This formation of Cu/Zn-Abeta complexes is thought to be aberrant as they have been detected only in AD, but not under healthy conditions. In this context, the understanding of how these metal ions interact with Abeta, their influence on structure and oligomerisation becomes an important issue for AD. Moreover, the mechanism of ROS production by Cu-Abeta in relation to its aggregation state, as well as metal exchange reaction from and to Abeta are crucial in order to understand why Abeta oligomers are highly toxic and why Abeta binding to Cu and Zn was only observed in AD. We hypothized that proteins able to retrieve the aberrant metal-binding to Abeta under healthy conditions but fail in AD might be involved. Metallothionein-3 and serum albumin might play this role, as they are highly abundant and strongly bind metal ions. Methods: In vitro biophysical techniques and studies in neuroblastoma cell culture were employed to understand the interaction of two of the most abundant metal-binding proteins, metallothionein and serum albumin and their capability of rescue metal-Abeta induced neurotoxicity. Results: In vitro experiments show that metallothionein and serum albumin are able to withdraw Cu ions from soluble and aggregated Abeta and suppress the ROS production of Cu-Abeta. Studies in cell culture confirmed the protection of these proteins against Cu-Abeta induced ROS and cell death. Metallothionein was more efficient then serum albumin. Moreover, metallothionein is also able to transfer zinc(II) to Abeta which modulates the aggregation behavior. This is enhanced under oxidative stress conditions. Conclusions: The results suggests that metallothioneins and perhaps also serum albumin are native protectors against the aberrant metal-binding to Abeta and hence neurotoxicity. Under oxidative stress conditions this activity might be reduced and favors the development of AD.