OVEREXPRESSION OF TAU-PROTEIN INHIBITS KINESIN-DEPENDENT TRAFFICKING OF VESICLES, MITOCHONDRIA, AND ENDOPLASMIC-RETICULUM - IMPLICATIONS FOR ALZHEIMERS-DISEASE

The neuronal microtubule-associated protein tau plays an important rol e in establishing cell polarity by stabilizing axonal microtubules tha t serve as tracks for motor-protein-driven transport processes. To inv estigate the role of tau in intracellular transport, we studied the ef fects of tau expression in stably transfected CHO cells and differenti ated neuroblastoma N2a cells. Tau causes a change in cell shape, retar ds cell growth, and dramatically alters the distribution of various or ganelles, known to be transported via microtubule-dependent motor prot eins. Mitochondria fail to be transported to peripheral cell compartme nts and cluster in the vicinity of the microtubule-organizing center. The endoplasmic reticulum becomes less dense and no longer extends to the cell periphery. In differentiated N2a cells, the overexpression of tau leads to the disappearance of mitochondria from the neurites. The se effects are caused by tau's binding to microtubules and slowing dow n intracellular transport by preferential impairment of plus-end-direc ted transport mediated by kinesin-like motor proteins. Since in Alzhei mer's disease tau protein is elevated and mislocalized, these observat ions point to a possible cause for the gradual degeneration of neurons .