Cell - Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models

Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models
Cell, Volume 142, Issue 3, 387-397, 22 July 2010
Copyright 2010 Elsevier Inc. All rights reserved.
10.1016/j.cell.2010.06.036

Referred to by: Fyn-Tau-Amyloid: A Toxic Triad

Authors
Lars M. Ittner, Yazi D. Ke, Fabien Delerue, Mian Bi, Amadeus Gladbach, Janet van Eersel, Heidrun Wölfing, Billy C. Chieng, MacDonald J. Christie, Ian A. Napier, Anne Eckert, Matthias Staufenbiel, Edna Hardeman, Jürgen GötzSee AffiliationsHint: Rollover Authors and Affiliations Alzheimer's and Parkinson's Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Sydney NSW 2050, Australia Neuropharmacology Laboratory, Brain and Mind Research Institute, University of Sydney, Sydney NSW 2050, Australia Neurobiology Research Laboratory, Psychiatric University Clinic, University of Basel, Basel CH-4025, Switzerland Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland Neuromuscular and Regenerative Medicine Unit, University of New South Wales, Sydney NSW 2052, Australia Corresponding author These authors contributed equally to this work

Highlights
•Expression of truncated tau in mice reveals dendritic functions of tau
•Truncated tau prevents premature death and memory deficits in Aβ-forming APP23 mice
•Postsynaptic localization of the kinase Fyn is tau dependent
•Fyn-mediated interaction between NMDAR and PSD-95 is required for Aβ toxicity

Summary
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) and tau deposition in brain. It has emerged that Aβ toxicity is tau dependent, although mechanistically this link remains unclear. Here, we show that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR). Missorting of tau in transgenic mice expressing truncated tau (tau) and absence of tau in tau/ mice both disrupt postsynaptic targeting of Fyn. This uncouples NR-mediated excitotoxicity and hence mitigates Aβ toxicity. tau expression and tau deficiency prevent memory deficits and improve survival in Aβ-forming APP23 mice, a model of AD. These deficits are also fully rescued with a peptide that uncouples the Fyn-mediated interaction of NR and PSD-95 in vivo. Our findings suggest that this dendritic role of tau confers Aβ toxicity at the postsynapse with direct implications for pathogenesis and treatment of AD.

10.1016/j.cell.2010.06.036
-1Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions.
Aarts, M., Liu, Y., Liu, L., Besshoh, S., Arundine, M., Gurd, J.W., Wang, Y.T., Salter, M.W., and Tymianski, M. (2002)
Science
298, 846850. View at PubMedView at PublisherA tale about tau.
Ashe, K.H. (2007)
N. Engl. J. Med.
357, 933935. View at PubMedView at PublisherTau-mediated neurodegeneration in Alzheimer's disease and related disorders.
Ballatore, C., Lee, V.M., and Trojanowski, J.Q. (2007)
Nat. Rev. Neurosci.
8, 663672. View at PubMedClusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease.
Busche, M.A., Eichhoff, G., Adelsberger, H., Abramowski, D., Wiederhold, K.H., Haass, C., Staufenbiel, M., Konnerth, A., and Garaschuk, O. (2008)
Science
321, 16861689. View at PubMedView at PublisherTau protein binds to microtubules through a flexible array of distributed weak sites.
Butner, K.A., and Kirschner, M.W. (1991)
J. Cell Biol.
115, 717730. View at PubMedView at PublisherNeuron loss in APP transgenic mice.
Calhoun, M.E., Wiederhold, K.H., Abramowski, D., Phinney, A.L., Probst, A., Sturchler-Pierrat, C., Staufenbiel, M., Sommer, B., and Jucker, M. (1998)
Nature
395, 755756. View at PubMedView at PublisherFyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice.
Chin, J., Palop, J.J., Yu, G.Q., Kojima, N., Masliah, E., and Mucke, L. (2004)
J. Neurosci.
24, 46924697. View at PubMedView at PublisherFyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease.
Chin, J., Palop, J.J., Puoliväli, J., Massaro, C., Bien-Ly, N., Gerstein, H., Scearce-Levie, K., Masliah, E., and Mucke, L. (2005)
J. Neurosci.
25, 96949703. View at PubMedView at PublisherEarly-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695.
Chishti, M.A., Yang, D.S., Janus, C., Phinney, A.L., Horne, P., Pearson, J., Strome, R., Zuker, N., Loukides, J., and French, J., et al. (2001)
J. Biol. Chem.
276, 2156221570. View at PubMedView at PublisherThe repeat region of microtubule-associated protein tau forms part of the core of the paired helical filament of Alzheimer's disease.
Crowther, T., Goedert, M., and Wischik, C.M. (1989)
Ann. Med.
21, 127132. View at PubMedView at PublisherDifferential regulation of dynein and kinesin motor proteins by tau.
Dixit, R., Ross, J.L., Goldman, Y.E., and Holzbaur, E.L. (2008)
Science
319, 10861089. View at PubMedView at PublisherModulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau.
Drechsel, D.N., Hyman, A.A., Cobb, M.H., and Kirschner, M.W. (1992)
Mol. Biol. Cell
3, 11411154. View at PubMedCcr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease.
El Khoury, J., Toft, M., Hickman, S.E., Means, T.K., Terada, K., Geula, C., and Luster, A.D. (2007)
Nat. Med.
13, 432438. View at PubMedView at PublisherTau phosphorylation, tangles, and neurodegeneration: the chicken or the egg?.
Geschwind, D.H. (2003)
Neuron
40, 457460. View at PubMedView at PublisherCloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau.
Goedert, M., Wischik, C.M., Crowther, R.A., Walker, J.E., and Klug, A. (1988)
Proc. Natl. Acad. Sci. USA
85, 40514055. View at PubMedView at PublisherAnimal models of Alzheimer's disease and frontotemporal dementia.
Götz, J., and Ittner, L.M. (2008)
Nat. Rev. Neurosci.
9, 532544. View at PubMedTau filament formation in transgenic mice expressing P301L tau.
Götz, J., Chen, F., Barmettler, R., and Nitsch, R.M. (2001)
J. Biol. Chem.
276, 529534. View at PubMedView at PublisherFormation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.
Götz, J., Chen, F., van Dorpe, J., and Nitsch, R.M. (2001)
Science
293, 14911495. View at PubMedView at PublisherImpaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice.
Grant, S.G., O'Dell, T.J., Karl, K.A., Stein, P.L., Soriano, P., and Kandel, E.R. (1992)
Science
258, 19031910. View at PubMedAmyloid beta-peptide is produced by cultured cells during normal metabolism.
Haass, C., Schlossmacher, M.G., Hung, A.Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B.L., Lieberburg, I., Koo, E.H., Schenk, D., and Teplow, D.B., et al. (1992)
Nature
359, 322325. View at PubMedView at PublisherCorrelative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., and Cole, G. (1996)
Science
274, 99102. View at PubMedView at PublisherProgressive age-related impairment of cognitive behavior in APP23 transgenic mice.
Kelly, P.H., Bondolfi, L., Hunziker, D., Schlecht, H.P., Carver, K., Maguire, E., Abramowski, D., Wiederhold, K.H., Sturchler-Pierrat, C., and Jucker, M., et al. (2003)
Neurobiol. Aging
24, 365378. View at PubMedView at PublisherPDZ domain proteins of synapses.
Kim, E., and Sheng, M. (2004)
Nat. Rev. Neurosci.
5, 771781. View at PubMedHigher seizure susceptibility and enhanced tyrosine phosphorylation of N-methyl-D-aspartate receptor subunit 2B in fyn transgenic mice.
Kojima, N., Ishibashi, H., Obata, K., and Kandel, E.R. (1998)
Learn. Mem.
5, 429445. View at PubMedDomain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95.
Kornau, H.C., Schenker, L.T., Kennedy, M.B., and Seeburg, P.H. (1995)
Science
269, 17371740. View at PubMedStructural stability of paired helical filaments requires microtubule-binding domains of tau: a model for self-association.
Ksiezak-Reding, H., and Yen, S.H. (1991)
Neuron
6, 717728. View at PubMedView at PublisherThe evolution of A beta peptide burden in the APP23 transgenic mice: implications for A beta deposition in Alzheimer disease.
Kuo, Y.M., Beach, T.G., Sue, L.I., Scott, S., Layne, K.J., Kokjohn, T.A., Kalback, W.M., Luehrs, D.C., Vishnivetskaya, T.A., and Abramowski, D., et al. (2001)
Mol. Med.
7, 609618. View at PubMedNeurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen.
Lalonde, R., Dumont, M., Staufenbiel, M., and Strazielle, C. (2005)
Behav. Brain Res.
157, 9198. View at PubMedView at PublisherThe primary structure and heterogeneity of tau protein from mouse brain.
Lee, G., Cowan, N., and Kirschner, M. (1988)
Science
239, 285288. View at PubMedTau interacts with src-family non-receptor tyrosine kinases.
Lee, G., Newman, S.T., Gard, D.L., Band, H., and Panchamoorthy, G. (1998)
J. Cell Sci.
111, 31673177. View at PubMedEnhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death.
Leissring, M.A., Farris, W., Chang, A.Y., Walsh, D.M., Wu, X., Sun, X., Frosch, M.P., and Selkoe, D.J. (2003)
Neuron
40, 10871093. View at PubMedView at PublisherEnhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.
Lewis, J., Dickson, D.W., Lin, W.L., Chisholm, L., Corral, A., Jones, G., Yen, S.H., Sahara, N., Skipper, L., and Yager, D., et al. (2001)
Science
293, 14871491. View at PubMedView at PublisherInteraction of tau with the neural membrane cortex is regulated by phosphorylation at sites that are modified in paired helical filaments.
Maas, T., Eidenmüller, J., and Brandt, R. (2000)
J. Biol. Chem.
275, 1573315740. View at PubMedView at PublisherAmyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy.
Minkeviciene, R., Rheims, S., Dobszay, M.B., Zilberter, M., Hartikainen, J., Fülöp, L., Penke, B., Zilberter, Y., Harkany, T., Pitkänen, A., et al. (2009)
J. Neurosci.
29, 34533462. View at PubMedView at PublisherHigh-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.
Mucke, L., Masliah, E., Yu, G.Q., Mallory, M., Rockenstein, E.M., Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K., and McConlogue, L. (2000)
J. Neurosci.
20, 40504058. View at PubMedCharacterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor.
Nakazawa, T., Komai, S., Tezuka, T., Hisatsune, C., Umemori, H., Semba, K., Mishina, M., Manabe, T., and Yamamoto, T. (2001)
J. Biol. Chem.
276, 693699. View at PubMedView at PublisherEpilepsy and cognitive impairments in Alzheimer disease.
Palop, J.J., and Mucke, L. (2009)
Arch. Neurol.
66, 435440. View at PubMedView at PublisherAberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease.
Palop, J.J., Chin, J., Roberson, E.D., Wang, J., Thwin, M.T., Bien-Ly, N., Yoo, J., Ho, K.O., Yu, G.Q., and Kreitzer, A., et al. (2007)
Neuron
55, 697711. View at PubMedView at PublisherThe presynaptic particle web: ultrastructure, composition, dissolution, and reconstitution.
Phillips, G.R., Huang, J.K., Wang, Y., Tanaka, H., Shapiro, L., Zhang, W., Shan, W.S., Arndt, K., Frank, M., and Gordon, R.E., et al. (2001)
Neuron
32, 6377. View at PubMedView at PublisherReducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model.
Roberson, E.D., Scearce-Levie, K., Palop, J.J., Yan, F., Cheng, I.H., Wu, T., Gerstein, H., Yu, G.Q., and Mucke, L. (2007)
Science
316, 750754. View at PubMedView at PublisherMolecular determinants of NMDA receptor internalization.
Roche, K.W., Standley, S., McCallum, J., Dune Ly, C., Ehlers, M.D., and Wenthold, R.J. (2001)
Nat. Neurosci.
4, 794802. View at PubMedView at PublisherTyrosine phosphorylation of ionotropic glutamate receptors by Fyn or Src differentially modulates their susceptibility to calpain and enhances their binding to spectrin and PSD-95.
Rong, Y., Lu, X., Bernard, A., Khrestchatisky, M., and Baudry, M. (2001)
J. Neurochem.
79, 382390. View at PubMedView at PublisherAPP transgenic mice: the effect of active and passive immunotherapy in cognitive tasks.
Röskam, S., Neff, F., Schwarting, R., Bacher, M., and Dodel, R. (2010)
Neurosci. Biobehav. Rev.
34, 487499. View at PubMedView at PublisherSrc kinases: a hub for NMDA receptor regulation.
Salter, M.W., and Kalia, L.V. (2004)
Nat. Rev. Neurosci.
5, 317328. View at PubMedAlzheimer's disease: genotypes, phenotypes, and treatments.
Selkoe, D.J. (1997)
Science
275, 630631. View at PubMedView at PublisherAlzheimer's disease is a synaptic failure.
Selkoe, D.J. (2002)
Science
298, 789791. View at PubMedView at PublisherAmyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
Shankar, G.M., Li, S., Mehta, T.H., Garcia-Munoz, A., Shepardson, N.E., Smith, I., Brett, F.M., Farrell, M.A., Rowan, M.J., and Lemere, C.A., et al. (2008)
Nat. Med.
14, 837842. View at PubMedView at PublisherTwo amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.
Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.H., Mistl, C., Rothacher, S., Ledermann, B., Bürki, K., Frey, P., and Paganetti, P.A., et al. (1997)
Proc. Natl. Acad. Sci. USA
94, 1328713292. View at PubMedView at PublisherPSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A.
Tezuka, T., Umemori, H., Akiyama, T., Nakanishi, S., and Yamamoto, T. (1999)
Proc. Natl. Acad. Sci. USA
96, 435440. View at PubMedView at PublisherNeurotrophins are required for nerve growth during development.
Tucker, K.L., Meyer, M., and Barde, Y.A. (2001)
Nat. Neurosci.
4, 2937. View at PubMedView at PublisherAge-dependent cognitive decline in the APP23 model precedes amyloid deposition.
Van Dam, D., D'Hooge, R., Staufenbiel, M., Van Ginneken, C., Van Meir, F., and De Deyn, P.P. (2003)
Eur. J. Neurosci.
17, 388396. View at PubMedView at PublisherA protein factor essential for microtubule assembly.
Weingarten, M.D., Lockwood, A.H., Hwo, S.Y., and Kirschner, M.W. (1975)
Proc. Natl. Acad. Sci. USA
72, 18581862. View at PubMedView at PublisherA role for Fyn tyrosine kinase in the suckling behaviour of neonatal mice.
Yagi, T., Aizawa, S., Tokunaga, T., Shigetani, Y., Takeda, N., and Ikawa, Y. (1993)
Nature
366, 742745. View at PubMedView at PublisherRole of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease.
Zhao, L., Ma, Q.L., Calon, F., Harris-White, M.E., Yang, F., Lim, G.P., Morihara, T., Ubeda, O.J., Ambegaokar, S., and Hansen, J.E., et al. (2006)
Nat. Neurosci.
9, 234242. View at PubMedView at PublisherCalabrese, B., and Halpain, S. (2005). Essential role for the PKC target MARCKS in maintaining dendritic spine morphology. Neuron 48, 7790.
Fath, T., Ke, Y.D., Gunning, P., Götz, J., and Ittner, L.M. (2009). Primary support cultures of hippocampal and substantia nigra neurons. Nat. Protoc. 4, 7885.
Götz, J., Probst, A., Spillantini, M.G., Schäfer, T., Jakes, R., Bürki, K., and Goedert, M. (1995). Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J. 14, 13041313.
Ittner, L.M., and Götz, J. (2007). Pronuclear injection for the production of transgenic mice. Nat. Protoc. 2, 12061215.
Ittner, L.M., Ke, Y.D., and Götz, J. (2009). Phosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease. J. Biol. Chem. 284, 2090920916.
Ittner, L.M., Koller, D., Muff, R., Fischer, J.A., and Born, W. (2005a). The N-terminal extracellular domain 23-60 of the calcitonin receptor-like receptor in chimeras with the parathyroid hormone receptor mediates association with receptor activity-modifying protein 1. Biochemistry 44, 57495754.
Ittner, L.M., Wurdak, H., Schwerdtfeger, K., Kunz, T., Ille, F., Leveen, P., Hjalt, T.A., Suter, U., Karlsson, S., Hafezi, F., et al. (2005b). Compound developmental eye disorders following inactivation of TGFbeta signaling in neural-crest stem cells. J. Biol. 4, 11.
Krupka, N., Strappe, P., Götz, J., and Ittner, L.M. (2010). Gateway-compatible lentiviral transfer vectors for ubiquitin promoter driven expression of fluorescent fusion proteins. Plasmid 63, 155160.
Lambert, M.P., Barlow, A.K., Chromy, B.A., Edwards, C., Freed, R., Liosatos, M., Morgan, T.E., Rozovsky, I., Trommer, B., Viola, K.L., et al. (1998). Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95, 64486453.
Probst, A., Götz, J., Wiederhold, K.H., Tolnay, M., Mistl, C., Jaton, A.L., Hong, M., Ishihara, T., Lee, V.M., Trojanowski, J.Q., et al. (2000). Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol. 99, 469481.
Rao, A., and Steward, O. (1991). Evidence that protein constituents of postsynaptic membrane specializations are locally synthesized: analysis of proteins synthesized within synaptosomes. J. Neurosci. 11, 28812895.
Rapoport, M., Dawson, H.N., Binder, L.I., Vitek, M.P., and Ferreira, A. (2002). Tau is essential to beta -amyloid-induced neurotoxicity. Proc. Natl. Acad. Sci. USA 99, 63646369.



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Cell - Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models