title: Region-specific dendritic simplification induced by Aβ, mediated by tau via dysregulation of microtubule dynamics: a mechanistic distinct event from other neurodegenerative processes.
abstract: BACKGROUND
  Dendritic simplification, a key feature of the neurodegenerative triad of Alzheimer's disease (AD) in addition to spine changes and neuron loss, occurs in a region-specific manner. However, it is unknown how changes in dendritic complexity are mediated and how they relate to spine changes and neuron loss.
  
  
  RESULTS
  To investigate the mechanisms of dendritic simplification in an authentic CNS environment we employed an ex vivo model, based on targeted expression of enhanced green fluorescent protein (EGFP)-tagged constructs in organotypic hippocampal slices of mice. Algorithm-based 3D reconstruction of whole neuron morphology in different hippocampal regions was performed on slices from APPSDL-transgenic and control animals. We demonstrate that induction of dendritic simplification requires the combined action of amyloid beta (Aβ) and human tau. Simplification is restricted to principal neurons of the CA1 region, recapitulating the region specificity in AD patients, and occurs at sites of Schaffer collateral input. We report that γ-secretase inhibition and treatment with the NMDA-receptor antagonist, CPP, counteract dendritic simplification. The microtubule-stabilizing drug epothilone D (EpoD) induces simplification in control cultures per se. Similar morphological changes were induced by a phosphoblocking tau construct, which also increases microtubule stability. In fact, low nanomolar concentrations of naturally secreted Aβ decreased phosphorylation at S262 in a cellular model, a site which is known to directly modulate tau-microtubule interactions.
  
  
  CONCLUSIONS
  The data provide evidence that dendritic simplification is mechanistically distinct from other neurodegenerative events and involves microtubule stabilization by dendritic tau, which becomes dephosphorylated at certain sites. They imply that treatments leading to an overall decrease of tau phosphorylation might have a negative impact on neuronal connectivity.
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076, Osnabrück, Germany. golovyashkina@biologie.uni-osnabrueck.de.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Golovyashkina
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076, Osnabrück, Germany. penazzi@biologie.uni-osnabrueck.de.
authors.forename: Lorène
authors.initials: L
authors.lastname: Penazzi
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19014, USA. bcarlo@sas.upenn.edu.|Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. bcarlo@sas.upenn.edu.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19014, USA. smithab@sas.upenn.edu.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076, Osnabrück, Germany. bakota@biologie.uni-osnabrueck.de.
authors.forename: Lidia
authors.initials: L
authors.lastname: Bakota
authors.affiliation: Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076, Osnabrück, Germany. brandt@biologie.uni-osnabrueck.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Brandt
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D003712:Dendrites / Q000378:metabolism / Q000473:pathology*; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008870:Microtubules / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D013569:Synapses / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins