P2-135: Mechanisms of neuronal traffic inhibition by tau protein

Abstract

The missorting of Tau protein from the axonal to the somatodendritic compartment and loss of synapses are hallmarks of Alzheimer's disease which precede neuronal loss and the pathological aggregation of tau protein into neurofibrillary tangles. We are interested in the mechanisms by which Tau can affect the integrity of synapses. One major factor is the inhibition of movement of mitochondria by Tau which leads to mitochondrial dysfunction and energy deprivation (loss of ATP production). We have now studied the pathway of Tau's interference with mitochondrial transport. Primary hippocampal neurons were transfected with CFP-Tau, mitochondrial traffic and synaptic integrity was observed by time-resolved confocal microscopy, followed by thin-sectioning electron microscopy to visualize the state of mitochondria, synapses, and the cytoskeleton. The results show that Tau operates on two distinct levels. One is a direct inhibition mechanism whereby bound Tau covers the microtubule surface and consequently interferes with the attachment of motor proteins. The second is an indirect inhibition mechanism which is based on the higher stability of microtubules when Tau is increased. This leads to a reduced level of tubulin subunits in the cytosol, which in turn causes the upregulation of tubulin synthesis (Cleveland et al., Nature 1983). This causes an increase in microtubule density, the microtubules become tightly bundled so that mitochondria can no longer move freely along axons and dendrites. The example illustrates how an improvement of microtubule stability can cause traffic deficits in neurons, rather than curing them. Research supported by MPG and DFG.