Neurobiology of Aging 30 (2009) 22–33 A Caenorhabditis elegans model of tau hyperphosphorylation: Induction of developmental defects by transgenic overexpression of Alzheimer’s disease-like modified tau Roland Brandt a,∗ , Aikaterini Gergou a , Irene Wacker b , Thomas Fath a,c , Harald Hutter b a Department of Neurobiology, University of Osnabr¨ uck, Barbarastraße 11, D-49076 Osnabr¨ uck, Germany b Max Planck Institute for Medical Research, 69120 Heidelberg, Germany c Interdisziplin¨ ares Zentrum f¨ ur Neurowissenschaften, Department of Neurobiology, University of Heidelberg, 69120 Heidelberg, Germany Received 10 July 2006; received in revised form 3 May 2007; accepted 15 May 2007 Available online 22 June 2007 Abstract The microtubule-associated tau proteins become functionally and structurally altered in Alzheimer’s disease (AD). To analyze tau modifi- cation and its role in a non-vertebrate animal model, we produced transgenic Caenorhabditis elegans strains with a panneuronal expression of human tau and a pseudohyperphosphorylated (PHP) tau construct that mimics AD-relevant tau modification. We show that human tau in C. elegans becomes highly phosphorylated and exhibits conformational changes similar to PHP tau and human PHF tau. Both, wt tau and PHP tau induced a progressive age-dependent development of a phenotype of uncoordinated locomotion (unc) in the absence of neuronal degeneration. However, only PHP tau induced a defective pattern of motor neuron development as indicated by the presence of gaps in the dorsal cord, commissures on the wrong side and local broadening of axons. The data indicate that C. elegans is capable of highly phosphorylating human tau to an AD-like state whereas only stable disease-like tau modification induce developmental defects suggesting a specific interference of pathologic tau with intracellular mechanisms of axonal outgrowth and pathfinding. © 2007 Elsevier Inc. All rights reserved. Keywords: Tauopathy; Neurodegenerative disease; Animal model; Cytoskeleton; Phosphorylation; Aggregation 1. Introduction Aggregation and abnormal phosphorylation of the microtubule-associated protein (MAP) tau are histopatho- logical hallmarks of several neurodegenerative diseases now collectively called tauopathies (Goedert and Jakes, 2005; Iqbal et al., 2005). Genetic analyses have established a clear cause-and-effect relationship between tau alteration and neu- ronal cell death and dementia in some tauopathies such as frontotemporal dementia and parkinsonism linked to chro- mosome 17 (FTDP-17), but the mechanisms, which render ∗ Corresponding author. Tel.: +49 541 969 2338; fax: +49 541 969 2354. E-mail address: brandt@biologie.uni-osnabrueck.de (R. Brandt). tau to become a toxic agent are still unclear. In particular this is true for the most common tauopathy, Alzheimer’s disease (AD), where no mutations in the tau gene have been observed so far. Increased phosphorylation of tau at selected sites (“hyper- phosphorylation”) is considered one of the earliest signs of neuronal degeneration and appears to precede tau aggrega- tion (Braak et al., 1994). From the distribution of phosphates in hyperphosphorylated tau it appears likely that hyperphos- phorylation results from the concerted action of many kinases and phosphatases rather than from the activity of any indi- vidual kinase (Stoothoff and Johnson, 2005). Although tau aggregation is closely associated with abnormal tau phospho- rylation in disease progression, the role of phosphorylation in the neurodegenerative process is still unclear. Important 0197-4580/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2007.05.011