Dr. Eva-Maria Mandelkow

Prof. Dr. Eckhard Mandelkow

Group Leaders

German Center for Neurodegenerative Diseases (DZNE)
Ludwig-Erhard-Allee 2
53175 Bonn

+49 (0) 228 / 43302-630
+49 (0) 228 / 43302-543 (Secretary)
+49 (0) 228 / 43302-699

Selected Publications

Selected publications by category:

The complete list of publications of both group leaders can be foundhere.

0. Reviews

1. Tau pathology, cell and animal models

2. Tau aggregation inhibitors

3. Tau structure, phosphorylation and aggregation

4. Protein kinases, MARK/Par-1

5. Motor proteins, kinesin

6. Microtubule structure and assembly

0. Reviews

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration.

Mandelkow, E.M., Mandelkow, E. (2012). In: "The Biology of Alzheimer Disease"., editors D. Selkoe, E. Mandelkow, D. Holtzman. Cold Spring Harbor Persp. Med., pp.133-157. doi: 10.1101/cshperspect.a006247

Lest we forget you - methylene blue.

Schirmer, R. H., Adler, H., Pickhardt, M., Mandelkow, E (2011). Neurobiol. Aging 2325.e7-2325.e16.

Tau protein and tau aggregation inhibitors.

Bulic, B., Pickhardt, M., Mandelkow, E.-M., Mandelkow, E. (2010). Neuropharmacol. 59, 276-289.

Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases.

Marx A, Nugoor C, Panneerselvam S, Mandelkow E (2010). FASEB J. 24:1637-1648.

Proteolytic processing of Tau.

Wang, Y., Garg, S., Mandelkow, E.M., Mandelkow, E. (2010). Biochem. Soc. Transactions 38, 955-961.

The Tau of MARK: A polarized view of the cytoskeleton.

Matenia, D., Mandelkow, E.M. (2009). TiBS 34, 332-342.

Tau-based treatment strategies in neurodegenerative diseases.

Schneider, A., Mandelkow, E. (2008). Neurotherapeutics 5, 443-457.

Structural Principles of Tau and Alzheimer Paired Helical Filaments.

Mandelkow, E., von Bergen, M., Biernat, J., Mandelkow, E.-M. (2007). Brain Pathol. 17:83-90.

The structure of microtubule motors.

Marx, A., Müller, J., Mandelkow, E. (2005). Adv. Protein Chem. 71, 299-344.

1. Tau pathology, cell and animal models

Trehalose enhances the degradation of Tau through the autophagy pathway in neurons.

Krüger, U., Wang, Y., Kumar, S., Mandelkow, E.M. (2011). Neurobiology of Aging [Epub ahead of print]

Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration.

Li, X., Kumar, Y., Zempel,, H., Mandelkow, E. M., Biernat, J., Mandelkow, E. (2011). EMBO J. 30, 4825-4837.

Tau-Induced defects in synaptic plasticity, learning and memory are reversible in a regulatable transgenic mouse model.

Sydow A., van der Jeugd A., Zheng, F., Ahmed T, Balschun D., Petrova O., Drexler D., Zhou L., Rune G., Mandelkow E., d'Hooge R., Alzheimer C., Mandelkow E.M. (2011). J. Neurosci. 31, 2511-2525.

Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines.

Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010). J. Neurosci. 30, 11938-11950.

A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation.

Paquet, D., Bhat, R., Sydow, A., Mandelkow, E.-M., Berg, S., Hellberg, S., Fälting, J., Distel, M., Köster, R.W., Schmid, B., Haass, C. (2009). J. Clin. Investigation 119, 1382-1395.

Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing.

Wang, Y. P., Martinez-Vicente, M., Krüger, U., Kaushik, S., Wong, E., Mandelkow, E.M., Cuervo, A.M., Mandelkow, E. (2009). Human Molec. Genetics 18, 4153-4170.

The potential for beta structure in the repeat domain of Tau protein determines aggregation, synaptic decay, neuronal loss, and co-assembly with endogenous Tau in inducible mouse models of tauopathy.

Mocanu, M., Nissen, A. Eckermann, K., Khlistunova, I., Biernat, J, Drexler, D., Petrova, O., Schönig, K., Bujard, H., Mandelkow, E., Zhou, L., Rune, G., Mandelkow, E.M. (2008). J. Neurosci. 28, 737-748.

The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of Alzheimer tauopathy.

Eckermann, K., Mocanu, M., Khlistunova, I., Biernat, J, Nissen, A., Hofmann, A., Schönig, K., Bujard, H., Haemisch, A., Mandelkow, E., Zhou, L., Rune, G., Mandelkow, E.M. (2007). J. Biol. Chem. 282, 31755-31765.

Swimming against the tide: Mobility of the microtubule-associated protein Tau in neurons.

Konzack, S., Thies, E., Marx, A., Mandelkow, E.-M., Mandelkow, E. (2007). J. Neurosci. 27, 9916-9927.

Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model.

Wang, Y.P., Biernat, J., Pickhardt, M., Mandelkow, E., Mandelkow, E.-M. (2007). Proc. Natl. Acad. Sci. U.S.A. 104, 10252-10257.

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

Thies, E., Mandelkow, E.-M. (2007). J. Neurosci. 27, 2896-2907.

Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model.

Wang, Y.P., Biernat, J., Pickhardt, M., Mandelkow, E., Mandelkow, E.-M. (2007). Proc. Natl. Acad. Sci. U.S.A. 104, 10252-10257.

Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta.

Goldsbury, C., Mocanu, M., Thies, E., Kaether, C., Haass, C., Keller, P., Biernat, J., Mandelkow, E.-M., Mandelkow, E. (2006). Traffic 7, 873-888.

Inducible expression of tau in cell models of Alzheimer's disease: Aggregation is toxic to cells but can be rescued by inhibitor drugs.

Goldsbury, C., Mocanu, M., Thies, E., Kaether, C., Haass, C., Keller, P., Biernat, J., Mandelkow, E.-M., Mandelkow, E. (2006). Traffic 7, 873-888.

Overexpression of tau protein alters kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: Implications for Alzheimer's disease.

Ebneth, A., Godemann, R., Stamer, K., Illenberger, S., Trinczek, B., Mandelkow, E.-M., Mandelkow, E. (1998). J. Cell Biol. 143, 777-794.

A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads.

Braak, E., Braak, H., Mandelkow, E.-M. (1994). Acta Neuropath. 87, 554-567.

2. Tau aggregation inhibitors

N´-benzylidene-benzohydrazides as novel and selective tau-PHF ligands.

Taghavi, A., Nasir, S., Pickhardt, M., Heyny-von Haussen, R., Krause, S., Mall, G., Mandelkow, E., Mandelkow. E.M., Schmidt B. (2011). J. Alzheimer's Disease 27, 835-843.

Discovery of rhodanine-based tau aggregation inhibitors in cell models of tauopathy.

Bulic, B., Pickhardt, M., Khlistunova, I., Biernat, J., Mandelkow, E.-M., Mandelkow, E., Waldmann, H. (2007). Angew. Chem. Int. Ed. 46, 9215-9219.

Phenylthiazolyl-hydrazide and its derivatives as inhibitors of tau aggregation in vitro and in cells.

Pickhardt, M., Larbig, G., Khlistunova, I., Coksezen, A., Meyer, B., Mandelkow, E.-M., Schmidt, B., Mandelkow, E. (2007). Biochemistry 46, 10016-10023.

Anthraquinones inhibit tau aggregation and dissolve Alzheimer paired helical filaments in vitro and in cells.

Pickhardt, M., Gazova, Z., von Bergen, M., Khlistunova, I., Wang, Y.-P., Hascher, A., Mandelkow, E.-M., Biernat, J., Mandelkow, E. (2005). J. Biol. Chem. 280, 3628-3635.

3. Tau structure, phosphorylation and aggregation

Human Tau isoforms assemble into ribbon-like fibrils that display polymorphic structure and stability.

Wegmann S, Jung YJ, Chinnathambi S, Mandelkow EM, Mandelkow E, Müller D (2010). J. Biol. Chem. 285, 27302-27313.

Structural Polymorphism of 441-Residue Tau at Single Residue Resolution.

Mukrasch, M., Bibow, S., Korukottu, J., Jeganathan, S., Biernat, J., Griesinger, C., Mandelkow, E., Zweckstetter, M. (2009). PLOS Biology 7:e34.

Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC-1) conformation.

Jeganathan, S, Hascher, A., Chinnathambi, S., Biernat, J., Mandelkow, E.-M., Mandelkow, E. (2008). J. Biol. Chem.. 283, 32066-32076.

Global hairpin folding of tau in solution.

Jeganathan, S., von Bergen, M., Brutlach, H., Steinhoff, H.-J., Mandelkow, E. (2006). Biochemistry 45, 2283-2293.

Sites of tau important for aggregation populate beta structure and bind to microtubules and polyanions.

Mukrasch, M. D., Biernat, J., von Bergen, M., Griesinger, C., Mandelkow, E. and Zweckstetter, M. (2005).J. Biol. Chem. 280, 24978-24986.

Surface decoration of microtubules by human tau.

Santarella, R., Skiniotis, G., Goldie, K., Tittmann, P., Gross, H., Mandelkow, E.-M., Mandelkow, E., Hoenger, A. (2004). J. Mol. Biol. 339, 539-553.

Tau paired helical filaments from Alzheimer's disease brain and assembled in vitro contain beta structure in the core domain.

Barghorn, S., Davies, P., Mandelkow, E. (2004). Biochemistry 43, 1694-1703.

Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif (306-VQIVYK-311) forming beta structure.

von Bergen, M., Friedhoff, P., Biernat, J., Heberle, J., Mandelkow, E.-M., Mandelkow, E. (2000). Proc. Natl. Acad. Sci. USA 97, 5129-5134.

Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments.

Schneider,A., Biernat,J., von Bergen, M., Mandelkow,E., Mandelkow,E.-M.(1999). Biochemistry 38, 3549-3558.

A nucleated assembly mechanism of Alzheimer paired helical filaments.

Friedhoff, P., von Bergen, M., Mandelkow, E.-M., Davies,P., Mandelkow, E.(1998). Proc. Natl. Acad. Sci. USA 95, 15712-15717.

RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments.

Kampers, T., Friedhoff, P., Biernat, J., Mandelkow, E.-M., Mandelkow, E. (1996). FEBS Letters 399, 344-349.

Domains of Tau Protein and Interactions with Microtubules.

Gustke,N., Trinczek,B., Biernat,J., Mandelkow,E.-M., Mandelkow, E. (1994). Biochemistry 33, 9511-9522.

Phosphorylation of serine 262 strongly reduces the binding of tau protein to microtubules: Distinction between PHF-like immunoreactivity and microtubule binding.

Biernat,J., Gustke,N., Drewes,G., Mandelkow,E.-M., Mandelkow, E. (1993). Neuron 11, 153-163.

Phosphorylation dependent interaction of neurofilament antibodies with tau protein: Epitopes, phosphorylation sites, and relationship with Alzheimer tau.

Lichtenberg-Kraag,B., Mandelkow,E.-M., Biernat,J., Steiner,B., Schröter,C., Gustke,N., Meyer,H., Mandelkow,E. (1992). Proc. Natl. Acad. Sci. USA 89, 5384-5388.

Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro.

Wille,H., Drewes,G., Biernat,J., Mandelkow,E.-M., Mandelkow, E. (1992). J. Cell Biol. 118, 573-584.

Phosphorylation of microtubule-associated protein tau: Identification of the site for Ca++-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles.

Steiner, B., Mandelkow, E.-M., Biernat, J., Gustke, N., Meyer, H.E., Schmidt, B., Mieskes, G., Söling, H.D., Drechsel, D., Kirschner, M.W., Goedert, M., Mandelkow, E. (1990). EMBO J. 9, 3539-3544.

4. Protein kinases, MARK/Par-1

MARK2 turns PINK1 on at T313, a mutation site in Parkinson disease: Effects on mitochondrial transport.

Matenia, D., Hempp, C., Timm, T., Eikhof, A., Mandelkow., E. M. (2012). J. Biol. Chem., [Epub ahead of print]

Microtubule affinity regulating kinase (MARK) activity in living neurons examined by a genetically encoded FRET/FLIM based biosensor: Inhibitors with therapeutic potential.

Timm, T., von Kries, J. P., Li, X., Zempel, H., Mandelkow, E., Mandelkow, E. M. (2011). J. Biol. Chem 286:41711-41722.

Spred1 and TESK1 - two new interaction partners of the kinase MARKK/TAO1 that mediate crosstalk between the microtubule and actin cytoskeleton.

Johne, C., Matenia, D., Li, X. Y., Timm, T., Balusamy, K., Mandelkow, E.-M. (2008). Mol. Biol. Cell 19, 1391-1403.

Structure of the catalytic and ubiquitin-associated domains of the protein kinase MARK / Par-1.

Panneerselvam, S., Marx, A., Mandelkow, E.-M., Mandelkow, E. (2006). Structure 14, 173-183.

PAK5 kinase is an inhibitor of MARK/Par-1 which leads to stable microtubules and dynamic actin.

Matenia, D., Griesshaber, B., Li, X-Y., Thiessen, A., Johne, C., Jiao, J., Mandelkow, E., Mandelkow, E.-M. (2005). Mol. Biol. Cell 16, 4410-4422.

MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons.

Mandelkow, E.-M., Thies, E., Trinczek, B., Biernat, J., Mandelkow, E. (2004). J. Cell Biol. 167, 99-110.

MARKK, a Ste-20-like kinase, activates the polarity-inducing kinase MARK/PAR-1.

Timm, T., Li, X.Y., Biernat, J., Jiao, J., Mandelkow, E., Vandekerckhove, J., Mandelkow, E.-M. (2003). EMBO J. 22, 5090-5101.

MARK - a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption.

Drewes, G., Ebneth, A., Preuss, U., Mandelkow, E.-M., Mandelkow, E. (1997). Cell 89, 297-308.

5. Motor proteins, kinesin

X-ray structure and microtubule interactions of the motor domain of Neurospora crassa NcKin3, a kinesin with unusual processivity.

Marx, A., Müller, J., Mandelkow, E.-M., Woehlke, G., Bouchet-Marquis, C., Hoenger, A., Mandelkow, E. (2008). Biochemistry 47, 1848-1861.

Single-molecule investigation of the interference between kinesin and Tau on microtubules.

Seitz, A., Kojima, H., Oiwa, K., Mandelkow, E.-M., Song, Y.-H., Mandelkow, E. (2002). EMBO J. 21, 4896-4905.

Structure of a fast kinesin: Implications for the ATPase mechanism and interactions with microtubules.

Song, Y.-H., Marx, A., Müller, J., Woehlke, G., Schliwa, M., Krebs, A., Hoenger, A., Mandelkow, E. (2001). EMBO J. 20, 6213-6225.

Image reconstructions of microtubules decorated with monomeric and dimeric kinesins: Comparison with X-ray structure and implications for motility.

Hoenger, A., Sack, S., Thormählen, M., Marx, A., Müller, J., Gross, H., Mandelkow, E. (1998). J. Cell Biol. 141, 419-430.

The crystal structure of dimeric kinesin and implications for microtubule-dependent motility.

Kozielski, F., Sack, S., Marx, A., Thormählen, M., Schönbrunn, E., Biou, V., Thompson, A., Mandelkow, E.-M., Mandelkow, E. (1997). Cell 91, 985-994.

Recombinant kinesin motor domain binds to beta-tubulin and decorates microtubules with a B-surface lattice.

Song, Y.-H., Mandelkow, E. (1993). Proc. Natl. Acad. Sci. USA 90, 1671-1675.

6. Microtubule structure and assembly

Microtubule dynamics and microtubule caps: A time-resolved cryo-electron microscopy study.

Mandelkow, E.-M., Mandelkow, E., Milligan, R.A. (1991). J. Cell Biol. 114, 977-991.

Spatial patterns from oscillating microtubules.

Mandelkow, E., Mandelkow, E.-M., Hotani, H., Hess, B., Müller, S.C. (1989). Science 246, 1291-1293.

Dynamics of the microtubule oscillator: Role of nucleotides and tubulin-MAP interactions.

Mandelkow, E., Mandelkow, E.-M., Hotani, H., Hess, B., Müller, S.C. (1989). Science 246, 1291-1293.

Unstained microtubules studied by cryo-electron microscopy: Substructure, supertwist, and disassembly.

Mandelkow, E.-M., Mandelkow, E. (1985). J. Mol. Biol. 181, 123-135.

X-ray kinetic studies of microtubule assembly using synchrotron radiation.

Mandelkow, E.-M., Harmsen, A., Mandelkow, E., Bordas, J. (1980). Nature 287, 595-599.

Microtubule structure at low resolution by X-ray diffraction.

Mandelkow, E., Thomas, J., Cohen, C. (1977). Proc. Natl. Acad. Sci. USA 74, 3370-3374.

Tubulin hoops.

Mandelkow, E.-M., Mandelkow, E., Unwin, P.N.T., Cohen, C. (1977). Nature 265, 655-657.

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Areas of investigation/research focus

Neuronal cytoskeleton and Alzheimer disease

The two groups use complementary approaches to investigate the structure and function of the neuronal cytoskeleton, the neurofibrillary pathology of Alzheimer disease, and to develop therapeutic strategies.

The research includes biophysical methods to investigate protein structures and their aggregation pathways
(e.g. electron microscopy, X-ray scattering, spectroscopic methods), biochemical methods (protein interactions, enzyme activities), cell biological methods (development of cellular models of disease states, analysis of transport and aggregation mechanisms by imaging methods) and animal models of neurodegeneration
(e.g. transgenic mouse models of Tau-induced pathology).

Examples are:

  • microtubule assembly, interactions with associated proteins (MAPs) and motor proteins
  • Tau protein and pathological changes in Alzheimer disease and other "tauopathies"
  • Functional studies of protein kinases regulating the tau-microtubule interactions
  • Axonal transport mechanisms by motor proteins
  • Neuronal cell models of Alzheimer disease
  • Animal models of Alzheimer disease (transgenic mice, C. elegans)
  • Development of Tau aggregation inhibitors and modulators of Tau toxicity for therapy

"Morris Water Maze" swim test to probe memory

  • Mice are trained to find and  remember a platform (white circle).
  • Short path = good memory (left and right),
  • long path = poor memory (middle). 
(a) Control mouse remembers and finds platform quickly
(b) Mouse with tau pathology cannot remember and takes a long time to find platform
(c) Same mouse as (b), but after switching Tau off for 4 weeks: Memory has recovered back to normal

Kinwalk and KTdock

Motor protein kinesin walks along microtubule
Kinesin on microtubule