Increased Human Wildtype Tau Attenuates Axonal Transport Deficits Caused by Loss of APP in Mouse Models.

Amyloid precursor protein (APP) is implicated in axonal elongation, synaptic plasticity, and axonal transport. However, the role of APP on axonal transport in conjunction with the microtubule associated protein tau continues to be debated. Here we measured in vivo axonal transport in APP knockout mice with Manganese Enhanced MRI (MEMRI) to determine whether APP is necessary for maintaining normal axonal transport. We also tested how overexpression and mutations of tau affect axonal transport in the presence or absence of APP. In vivo axonal transport reduced significantly in the absence of functional APP. Overexpression of human wildtype tau maintained normal axonal transport and resulted in a transient compensation of axonal transport deficits in the absence of APP. Mutant R406Wtau in combination with the absence of APP compounded axonal transport deficits and these deficits persisted with age. These results indicate that APP is necessary for axonal transport, and overexpression of human wildtype tau can compensate for the absence of APP at an early age.

[1]  S. Snyder,et al.  Amyloid Precursor Proteins Inhibit Heme Oxygenase Activity and Augment Neurotoxicity in Alzheimer's Disease , 2000, Neuron.

[2]  G. Dawson,et al.  β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity , 1995, Cell.

[3]  Y. Larmet,et al.  Unraveling in vivo Functions of Amyloid Precursor Protein: Insights from Knockout and Knockdown Studies , 2006, Neurodegenerative Diseases.

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

[5]  Hui Zheng,et al.  In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease , 2007, NeuroImage.

[6]  W. Noble,et al.  Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. , 2009, Trends in molecular medicine.

[7]  Aidong Yuan,et al.  Axonal Transport Rates In Vivo Are Unaffected by Tau Deletion or Overexpression in Mice , 2008, The Journal of Neuroscience.

[8]  A. Takashima,et al.  c‐jun N‐terminal kinase hyperphosphorylates R406W tau at the PHF‐1 site during mitosis , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  G. Johnson,et al.  Mutant (R406W) Human Tau Is Hyperphosphorylated and Does Not Efficiently Bind Microtubules in a Neuronal Cortical Cell Model* , 2004, Journal of Biological Chemistry.

[10]  R. Jacobs,et al.  Role of neuronal activity and kinesin on tract tracing by manganese-enhanced MRI (MEMRI) , 2007, NeuroImage.

[11]  F. LaFerla,et al.  Pathways by which Abeta facilitates tau pathology. , 2006, Current Alzheimer research.

[12]  L. Goldstein,et al.  Disruption of Axonal Transport and Neuronal Viability by Amyloid Precursor Protein Mutations in Drosophila , 2001, Neuron.

[13]  T. Hashikawa,et al.  Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

[15]  K. Iverfeldt,et al.  Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors , 2009, Cellular and Molecular Life Sciences.

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

[17]  L. Goldstein,et al.  Kinesin-mediated axonal transport of a membrane compartment containing β-secretase and presenilin-1 requires APP , 2001, Nature.

[18]  Marcus Jang,et al.  A peptide zipcode sufficient for anterograde transport within amyloid precursor protein , 2006, Proceedings of the National Academy of Sciences.

[19]  M. Mattson,et al.  Ageing and neuronal vulnerability , 2006, Nature Reviews Neuroscience.

[20]  S. Lipton,et al.  Suppression of Cyclin-Dependent Kinase 5 Activation by Amyloid Precursor Protein: A Novel Excitoprotective Mechanism Involving Modulation of Tau Phosphorylation , 2005, The Journal of Neuroscience.

[21]  T. Gómez-Isla,et al.  Expression of stress‐activated kinases c‐Jun N‐terminal kinase (SAPK/JNK‐P) and p38 kinase (p38‐P), and tau hyperphosphorylation in neurites surrounding βA plaques in APP Tg2576 mice , 2004, Neuropathology and applied neurobiology.

[22]  G. Johnson,et al.  Tau phosphorylation in neuronal cell function and dysfunction , 2004, Journal of Cell Science.

[23]  D. Price,et al.  Axonal Transport, Amyloid Precursor Protein, Kinesin-1, and the Processing Apparatus: Revisited , 2005, The Journal of Neuroscience.

[24]  Bin Zhang,et al.  Retarded Axonal Transport of R406W Mutant Tau in Transgenic Mice with a Neurodegenerative Tauopathy , 2004, The Journal of Neuroscience.

[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]  A. Frankfurter,et al.  The distribution of tau in the mammalian central nervous system , 1985, The Journal of cell biology.

[27]  L. Binder,et al.  Phosphorylation determines two distinct species of Tau in the central nervous system. , 1987, Cell motility and the cytoskeleton.

[28]  C. Greer,et al.  Cytoskeletal organization of the developing mouse olfactory nerve layer , 2006, The Journal of comparative neurology.

[29]  L. Mucke,et al.  100 Years and Counting: Prospects for Defeating Alzheimer's Disease , 2006, Science.

[30]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[31]  J. Ávila,et al.  The FTDP‐17‐Linked Mutation R406W Abolishes the Interaction of Phosphorylated Tau with Microtubules , 2000, Journal of neurochemistry.

[32]  A. Takashima,et al.  Hyperphosphorylated tau in parahippocampal cortex impairs place learning in aged mice expressing wild‐type human tau , 2007, The EMBO journal.

[33]  Robert W Berry,et al.  Tau, tangles, and Alzheimer's disease. , 2005, Biochimica et biophysica acta.

[34]  N. Hirokawa,et al.  Altered microtubule organization in small-calibre axons of mice lacking tau protein , 1994, Nature.

[35]  L. Goldstein,et al.  Defective Kinesin Heavy Chain Behavior in Mouse Kinesin Light Chain Mutants , 1999, The Journal of cell biology.