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

Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta) and tau deposition in brain. It has emerged that Abeta 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 (Deltatau) and absence of tau in tau(-/-) mice both disrupt postsynaptic targeting of Fyn. This uncouples NR-mediated excitotoxicity and hence mitigates Abeta toxicity. Deltatau expression and tau deficiency prevent memory deficits and improve survival in Abeta-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 Abeta toxicity at the postsynapse with direct implications for pathogenesis and treatment of AD.

[1]  Anatol C. Kreitzer,et al.  Aberrant Excitatory Neuronal Activity and Compensatory Remodeling of Inhibitory Hippocampal Circuits in Mouse Models of Alzheimer's Disease , 2007, Neuron.

[2]  B. Sommer,et al.  Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Michael W. Salter,et al.  Src kinases: a hub for NMDA receptor regulation , 2004, Nature Reviews Neuroscience.

[4]  D. Geschwind.  Tau Phosphorylation, Tangles, and Neurodegeneration The Chicken or the Egg? , 2003, Neuron.

[5]  M. Baudry,et al.  Tyrosine phosphorylation of ionotropic glutamate receptors by Fyn or Src differentially modulates their susceptibility to calpain and enhances their binding to spectrin and PSD‐95 , 2001, Journal of neurochemistry.

[6]  Yingming Zhao,et al.  The Presynaptic Particle Web Ultrastructure, Composition, Dissolution, and Reconstitution , 2001, Neuron.

[7]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  M. Kirschner,et al.  Tau protein binds to microtubules through a flexible array of distributed weak sites , 1991, The Journal of cell biology.

[9]  Shoji Komai,et al.  Characterization of Fyn-mediated Tyrosine Phosphorylation Sites on GluRε2 (NR2B) Subunit of theN-Methyl-d-aspartate Receptor* , 2001, The Journal of Biological Chemistry.

[10]  C. Geula,et al.  Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease , 2007, Nature Medicine.

[11]  B. Sommer,et al.  Neuron loss in APP transgenic mice , 1998, Nature.

[12]  H. Band,et al.  Tau interacts with src-family non-receptor tyrosine kinases. , 1998, Journal of cell science.

[13]  E. Kandel,et al.  Higher seizure susceptibility and enhanced tyrosine phosphorylation of N-methyl-D-aspartate receptor subunit 2B in fyn transgenic mice. , 1998, Learning & memory.

[14]  Sylvain Rheims,et al.  Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy , 2009, The Journal of Neuroscience.

[15]  M. Kirschner,et al.  The primary structure and heterogeneity of tau protein from mouse brain. , 1988, Science.

[16]  D. Selkoe,et al.  Enhanced Proteolysis of β-Amyloid in APP Transgenic Mice Prevents Plaque Formation, Secondary Pathology, and Premature Death , 2003, Neuron.

[17]  M. Staufenbiel,et al.  Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen , 2005, Behavioural Brain Research.

[18]  S. Yen,et al.  Structural stability of paired helical filaments requires microtubule-binding domains of Tau: A model for self-association , 1991, Neuron.

[19]  L. Mucke,et al.  Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[20]  M. Goedert,et al.  The repeat region of microtubule-associated protein tau forms part of the core of the paired helical filament of Alzheimer's disease. , 1989, Annals of medicine.

[21]  J. Götz,et al.  Phosphorylated Tau Interacts with c-Jun N-terminal Kinase-interacting Protein 1 (JIP1) in Alzheimer Disease* , 2009, The Journal of Biological Chemistry.

[22]  O. Steward,et al.  Evidence that protein constituents of postsynaptic membrane specializations are locally synthesized: analysis of proteins synthesized within synaptosomes , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[23]  D. Selkoe,et al.  Alzheimer's Disease--Genotypes, Phenotype, and Treatments , 1997, Science.

[24]  M. Goedert,et al.  Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. , 1995, The EMBO journal.

[25]  M. Vitek,et al.  Tau is essential to β-amyloid-induced neurotoxicity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  R. D'Hooge,et al.  Age‐dependent cognitive decline in the APP23 model precedes amyloid deposition , 2003, The European journal of neuroscience.

[27]  D. Selkoe,et al.  Amyloid β-peptide is produced by cultured cells during normal metabolism , 1992, Nature.

[28]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[29]  J. Götz,et al.  Gateway-compatible lentiviral transfer vectors for ubiquitin promoter driven expression of fluorescent fusion proteins. , 2010, Plasmid.

[30]  J. Götz,et al.  Animal models of Alzheimer's disease and frontotemporal dementia , 2008, Nature Reviews Neuroscience.

[31]  D. Selkoe.  Alzheimer's disease: genotypes, phenotypes, and treatments. , 1997, Science.

[32]  Jürgen Götz,et al.  Pronuclear injection for the production of transgenic mice , 2007, Nature Protocols.

[33]  L. Mucke,et al.  Epilepsy and cognitive impairments in Alzheimer disease. , 2009, Archives of neurology.

[34]  Ram Dixit,et al.  Differential Regulation of Dynein and Kinesin Motor Proteins by Tau , 2008, Science.

[35]  Y. Barde,et al.  Neurotrophins are required for nerve growth during development , 2001, Nature Neuroscience.

[36]  E. Kandel,et al.  Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. , 1992, Science.

[37]  D. Teplow,et al.  Amyloid beta-peptide is produced by cultured cells during normal metabolism. , 1992, Nature.

[38]  M. Sheng,et al.  PDZ domain proteins of synapses , 2004, Nature Reviews Neuroscience.

[39]  S. Halpain,et al.  Essential Role for the PKC Target MARCKS in Maintaining Dendritic Spine Morphology , 2005, Neuron.

[40]  P. Seeburg,et al.  Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. , 1995, Science.

[41]  J. Walker,et al.  Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[42]  R. A. Crowther,et al.  Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein , 2000, Acta Neuropathologica.

[43]  T. Kunz,et al.  Compound developmental eye disorders following inactivation of TGFβ signaling in neural-crest stem cells , 2005, Journal of biology.

[44]  A. Hyman,et al.  Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. , 1992, Molecular biology of the cell.

[45]  B. Teter,et al.  Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease , 2006, Nature Neuroscience.

[46]  L. Mucke,et al.  Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model , 2007, Science.

[47]  S. Nakanishi,et al.  PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[48]  T. Yagi,et al.  A role for Fyn tyrosine kinase in the suckling behaviour of neonatal mice , 1993, Nature.

[49]  K. Ashe.  A tale about tau. , 2007, The New England journal of medicine.

[50]  J. Hardy,et al.  Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP , 2001, Science.

[51]  Kang Hu,et al.  High-Level Neuronal Expression of Aβ1–42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation , 2000, The Journal of Neuroscience.

[52]  R. Dodel,et al.  APP transgenic mice: The effect of active and passive immunotherapy in cognitive tasks , 2010, Neuroscience & Biobehavioral Reviews.

[53]  S. Turner,et al.  Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695* , 2001, The Journal of Biological Chemistry.

[54]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[55]  R. Nitsch,et al.  Tau Filament Formation in Transgenic Mice Expressing P301L Tau* , 2001, The Journal of Biological Chemistry.

[56]  R. Nitsch,et al.  Formation of Neurofibrillary Tangles in P301L Tau Transgenic Mice Induced by Aβ42 Fibrils , 2001, Science.

[57]  L. Mucke,et al.  Fyn Kinase Modulates Synaptotoxicity, But Not Aberrant Sprouting, in Human Amyloid Precursor Protein Transgenic Mice , 2004, The Journal of Neuroscience.

[58]  M. Kirschner,et al.  A protein factor essential for microtubule assembly. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Yitao Liu,et al.  Treatment of Ischemic Brain Damage by Perturbing NMDA Receptor- PSD-95 Protein Interactions , 2002, Science.

[60]  Jürgen Götz,et al.  Primary support cultures of hippocampal and substantia nigra neurons , 2008, Nature Protocols.

[61]  K. Roche,et al.  Molecular determinants of NMDA receptor internalization , 2001, Nature Neuroscience.

[62]  L. Ittner,et al.  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. , 2005, Biochemistry.

[63]  Arthur Konnerth,et al.  Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease , 2008, Science.

[64]  J. Trojanowski,et al.  Tau-mediated neurodegeneration in Alzheimer's disease and related disorders , 2007, Nature Reviews Neuroscience.

[65]  P. Kelly,et al.  Progressive age-related impairment of cognitive behavior in APP23 transgenic mice , 2003, Neurobiology of Aging.