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The Journal of Neuroscience, March 14, 2007, 27(11):2896-2907; doi:10.1523/JNEUROSCI.4674-06.2007

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Neurobiology of Disease
Missorting of Tau in Neurons Causes Degeneration of Synapses That Can Be Rescued by the Kinase MARK2/Par-1

Edda Thies and Eva-Maria Mandelkow

Max-Planck-Unit for Structural Molecular Biology, 22607 Hamburg, Germany

Correspondence should be addressed to Dr. Eva-Maria Mandelkow, Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany. Email: mandelkow{at}mpasmb.desy.de

Early hallmarks of Alzheimer's disease include the loss of synapses, which precedes the loss of neurons and the pathological phosphorylation and aggregation of tau protein. Mitochondrial dysfunction has been suggested as a reason, but evidence on the role of tau was lacking. Here, we show that transfection of tau in mature hippocampal neurons leads to an improper distribution of tau into the somatodendritic compartment with concomitant degeneration of synapses, as seen by the disappearance of spines and of presynaptic and postsynaptic markers. This is accompanied by transport inhibition of vesicles and organelles, concomitant with an increase and bundling of microtubules. Mitochondria degenerate, thus causing ATP levels to decrease. The tau-induced synaptic decay can be relieved by the activation of the kinase MARK2 (microtubule-associated protein/microtubule affinity regulating kinase 2)/Par-1 (protease-activated receptor 1), which can remove tau from the microtubule tracks and reverses the transport block. This leads to the rescue of dendritic spines, synapses, mitochondrial transport and ATP levels.

Key words: Alzheimer's disease; axonal traffic; microtubules; mitochondria; neurons; synapses; tau

Received Oct. 27, 2006; revised Jan. 30, 2007; accepted Feb. 2, 2007.

Correspondence should be addressed to Dr. Eva-Maria Mandelkow, Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany. Email: mandelkow{at}mpasmb.desy.de




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