Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1.
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.
Thies
Edda
E
Max-Planck-Unit for Structural Molecular Biology, 22607 Hamburg, Germany.
Mandelkow
Eva-Maria
EM
D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D001693:Biological Transport, Active / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D006624:Hippocampus / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008870:Microtubules / Q000201:enzymology; D009410:Nerve Degeneration / Q000201:enzymology* / Q000517:prevention & control; D009474:Neurons / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044463:Receptor, PAR-1 / Q000502:physiology*; D013569:Synapses / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
D044463:Receptor, PAR-1; D016875:tau Proteins; C094670:MARK2 protein, human; D017346:Protein Serine-Threonine Kinases