title: Early improved and late defective cognition is reflected by dendritic spines in Tau.P301L mice.
abstract: Cognitive demise correlates with progressive brain tauopathy in dementing patients. Improved cognition of young Tau.P301L mice contrasts with dysfunction later in life and remains unexplained (Boekhoorn et al., 2006). To unravel early mechanisms, we composed a correlative time line of clinical symptoms, cognitive defects, and biochemical and pathological traits, including comprehensive analysis of dendritic spines in specified regions of the cortex and hippocampus of young and adult Tau.P301L mice. Remarkably, young Tau.P301L mice have not more, but more mature spines than wild-type mice, revealing the anatomical substrate for their improved cognition and LTP. Spine maturation remained high in the hippocampus of adult Tau.P301L mice. However, spines regressed in length paralleling impaired cognition and increased Tau phosphorylation (Terwel et al., 2005). Conversely, spine maturation was unaffected in adult Tau.4R mice, while spine density was increased and length reduced similar to Tau.P301L mice. To explain how protein Tau promoted spinogenesis, we analyzed hippocampal synaptosomes and dendritic spines for mouse and human Tau. While synaptosomes were positive for both mouse and human Tau, weak variable reaction in spines was observed only after fixation according to Bouin. Mouse Tau was absent from spines in wild-type mice, dissociating the pathological actions of Tau in transgenic mice by relocalization into dendrites and spines from the physiological actions of protein Tau in axons only. We conclude that mutant protein Tau modulates cognition and morphology of spines similarly and in both directions, with pathology later in life coinciding with increased phosphorylation and relocalization of Tau from axons to soma and processes.
authors.affiliation: Laboratory of Experimental Genetics and Transgenesis/Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg, B-3000 Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Kremer
authors.forename: Hervé
authors.initials: H
authors.lastname: Maurin
authors.forename: David
authors.initials: D
authors.lastname: Demedts
authors.forename: Herman
authors.initials: H
authors.lastname: Devijver
authors.forename: Peter
authors.initials: P
authors.lastname: Borghgraef
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
mesh_terms: D000367:Age Factors; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000473:pathology*; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D049229:Dendritic Spines / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007930:Leucine / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000235:genetics; D011392:Proline / Q000235:genetics*; D013574:Synaptosomes / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; D016875:tau Proteins; C054562:yellow fluorescent protein, Bacteria; D011392:Proline; D007930:Leucine