Missorting of Tau in Neurons Causes Degeneration of Synapses That Can Be Rescued by the Kinase MARK2/Par-1
Open accessAbstract
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.
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Tau colocalizes with actin in differentiating PC12 cells, N2a cells and in the postsynaptic compartments of mature neurons.
“Tau colocalizes with actin in differentiating PC12 cells68, N2a cells69 and in the postsynaptic compartments of mature neurons70.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [70]
For citation 70, the 'Missorting of tau and effects on synapses' section (Fig. 1; page not provided) reports that F-actin fills postsynaptic spine heads and that expressed tau enters those spine heads in hippocampal neurons with mature synapses. The claim omits the crucial condition: tau was experimentally expressed and missorted; in untransfected neurons, the paper reports tau only in axons. Citations 68 and 69, attached to the PC12 and N2a claims, are not assessed here. (LLM, conf=0.87)
Experimental — accuracy not yet measuredWhen Tau is overexpressed in cortical neurons, tubulin synthesis is upregulated and MTs become more numerous and densely packed, resulting in inhibition of mitochondrial movement.
“When Tau is overexpressed in cortical neurons, tubulin synthesis is upregulated and MTs become more numerous and densely packed, resulting in inhibition of mitochondrial movement.”
From Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease (2012) · cites this paper as Thies and Mandelkow, 2007
The Microtubule bundling section reports increased tubulin production and denser, more numerous microtubules after tau transfection; the mitochondrial-movement section reports strongly inhibited movement. However, Materials and Methods identifies the cells as hippocampal, not cortical, neurons, and the Discussion describes increased microtubule density and bundling as a possible contributor to the transport defect rather than its established sole cause. Page numbers were not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredTau phosphorylation at Ser262/356 decreases tau's affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice.
“Tau phosphorylation at these sites decreases the protein’s affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice [18, 19, 25–27, 50–52].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [19]
The ‘Phosphorylation of tau by MARK2’ section reports that increased phosphorylation at tau’s KXGS motifs in cultured neurons is associated with detachment from microtubules. It does not identify Ser262/356 specifically or establish this effect in vitro, in transgenic Drosophila, or in transgenic mice; the Introduction mentions the animal models in connection with tau pathology, not this affinity finding. The supplied copy gives no page numbers for these passages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTau proteins detached from microtubules are prone to be phosphorylated at disease-associated sites.
“tau proteins detached from microtubules are prone to be phosphorylated at disease-associated sites [19, 25–28].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [19]
The 'Phosphorylation of tau by MARK2' section (page unavailable) links increased phosphorylation at KXGS motifs with tau’s detachment from microtubules. It does not show that tau already detached from microtubules is more prone to phosphorylation, or identify those motifs as disease-associated sites; the reported sequence is phosphorylation followed by detachment. (LLM, conf=0.79)
Experimental — accuracy not yet measuredPhosphorylation at Ser262 and Ser356 decreases tau binding to microtubules.
“Ser262 and Ser356 are located in the microtubule-binding domain, and phosphorylation at these sites decreases tau binding to microtubules [18, 19, 25, 26, 50, 51].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [19]
The “Phosphorylation of tau by MARK2” section links phosphorylation of KXGS motifs in tau’s repeat domain with detachment from microtubules, supporting the general binding claim. Our copy does not identify Ser262 and Ser356 specifically, so it does not establish the claim at that site-specific level; page numbers are unavailable. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Tau phosphorylation at specific sites has been shown to ameliorate tau-induced deficits and toxicity.
“Furthermore, tau phosphorylation at specific sites has been shown to ameliorate tau-induced deficits and toxicity (40)”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [40]
MARK-2 overexpression in primary neurons reduces tau-induced deficits by alleviating organelle and vesicle transport blockade.
“Furthermore, MARK-2 overexpression in primary neurons reduces tau-induced deficits by alleviating organelle and vesicle transport blockade (40,126).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [40]
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- Authors
- Thies, E., & Mandelkow, E.-M.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Corresponding author
- Mandelkow, Eva-Maria
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-03-14
- Volume
- 27
- Issue
- 11
- Pages
- 2896-2907
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6672561
- OpenAlex
- W2061538653
- Cited by
- 293
- References
- 7
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 9 · 2023: 9 · 2022: 14 · 2021: 13 · 2020: 15 · 2019: 14 · 2018: 18 · 2017: 15 · 2016: 13 · 2015: 12 · 2014: 16 · 2013: 17 · 2012: 22
- FWCI
- 13.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Max-Planck-Gesellschaft
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, synaptic degeneration, Alzheimer's disease, hippocampal neurons, dendritic spines, mitochondrial transport, mitochondrial dysfunction, microtubule bundling, vesicle trafficking, ATP depletion, tau phosphorylation
- MeSH terms
- Animals, Axonal Transport, Biological Transport, Active, Cell Line, Cells, Cultured, Hippocampus, Humans, Microtubules, Nerve Degeneration, Neurons, Synapses, tau Proteins, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Receptor, PAR-1, Rats
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