The major findings of this study are that redox-active Cu(II)-A¦Â causes pronounced axonal pathology in long-term neuronal cultures, including axonal fragmentation and the formation of hyperphosphorylated tau-immunoreactive axonal swellings. Notably, MAP-2 expressing dendritic processes remain largely un-affected by Cu(II)-A¦Â treatment. These dystrophic axonal manifestations resemble some of the characteristic neuritic pathology of the AD brain. We show that Cu(II)-A¦Â directly causes formation of intra-axonal swellings via the generation of free radicals and subsequent efflux of K+ out of neurons.
In summary, we report that redox-active Cu(II)-A¦Â can induce substantial neurodegenerative changes in mature neurons, and may have an important role to play in the slowly progressing pathogenesis of AD.