Dataset Information

Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1.

ABSTRACT: 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.

SUBMITTER: Thies E

PROVIDER: S-EPMC6672561 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1.

Thies Edda E Mandelkow Eva-Maria EM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20070301 11

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 sp ...[more]

PMID: 17360912

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Project description:Missorting of MAPT/Tau represents one of the early signs of neurodegeneration in Alzheimer disease. The triggers for this are still a matter of debate. Here we investigated the sorting mechanisms of endogenous MAPT in mature primary neurons using microfluidic chambers (MFCs) where cell compartments can be observed separately. Blocking protein degradation pathways with proteasomal or autophagy inhibitors dramatically increased the missorting of MAPT in dendrites on the neuritic side, suggesting that degradation of MAPT in dendrites is a major determinant for the physiological axonal distribution of MAPT. Such missorted dendritic MAPT differed in its phosphorylation pattern from axonal MAPT. By contrast, enhancing autophagy or proteasomal pathways strongly reduced MAPT missorting, thereby confirming the role of protein degradation pathways in the polar distribution of MAPT. Dendritic missorting of MAPT by blocking protein degradation resulted in the loss of spines but not in overall cell toxicity. Inhibition of local protein synthesis in dendrites eliminated the missorting of MAPT, indicating that the accumulation of dendritic MAPT is locally generated. In support of this, a substantial fraction of Mapt/Tau mRNA was detected in dendrites. Taken together, our results indicate that the autophagy and proteasomal pathways play important roles in fine-tuning dendritic MAPT levels and thereby prevent synaptic toxicity caused by MAPT accumulation. Abbreviations Ani: anisomycin; Baf: bafilomycin A1; BSA: bovine serum albumin; cAMP: cyclic adenosine monophosphate; CHX: cycloheximide; DMSO: dimethyl sulfoxide; DIV: days in vitro; Epo: epoxomicin; E18: embryonic day 18; FISH: fluorescence in situ hybridization; IgG: immunoglobulin; kDa: kilodalton; Lac: lactacystin; LDH: lactate dehydrogenase; MFC: microfluidic chambers; MAPs: microtubule-associated proteins; MAPT/Tau: microtubule-associated protein tau; PVDF: polyvinylidene difluoride; PBS: phosphate-buffered saline; PRKA: protein kinase AMP-activated; RD150: round device 150; RT: room temperature; SDS: sodium dodecyl sulfate; SEM: standard error of the mean; Wor: wortmannin.

Dataset Information

Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1.

Publications

Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1.

Similar Datasets

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