Figure 9.

The sequence of pathological events induced by annonacin in primary cultures of striatal neurons. Annonacin inhibited the NADH-quinone-oxidoreductase activity of mitochondrial complex I, leading to increased ROS and decreased ATP production. The latter appears to be responsible for the retrograde transport of tau from neurites to the cell soma and, consequently, microtubule breakdown, because the antioxidants trolox and NAC had no effect on cell death or the distribution of tau, whereas increasing ATP levels by the expression of the yeast NADH oxidase NDI1 or the stimulation of anaerobic glycolysis with high glucose concentrations prevented both cell death and the redistribution of tau. ATP depletion induced by the respiratory chain inhibitors MPP⁺ and 3-NP or by the mitochondrial uncoupler CCCP mimicked annonacin-induced cell death and redistribution of tau. Taxol prevented the redistribution of tau and mitochondria but not the cell death induced by annonacin, suggesting that, in this experimental model, the redistribution of tau to the cell body is not involved in either neuroprotective or neurodegenerative pathways. It may rather be considered to be a stigma characteristic of neuronal death induced by energy failure.