title: Age-dependent neuroinflammation and cognitive decline in a novel Ala152Thr-Tau transgenic mouse model of PSP and AD.
abstract: BACKGROUND
  Mutations of Tau are associated with several neurodegenerative disorders. Recently, the Tau mutation A152T was described as a novel risk factor for frontotemporal dementia spectrum disorders and Alzheimer disease. In vitro Tau-A152T shows a decreased binding to microtubules and a reduced tendency to form abnormal fibers.
  
  
  RESULTS
  To study the effects of this mutation we generated a mouse model expressing human full-length Tau with this mutation (hTau40(AT)). At young age (2-3 months) immunohistological analysis reveals pathological Tau conformation and Tau-hyperphosphorylation combined with Tau missorting into the somatodendritic compartment of neurons. With increasing age there is Tau aggregation including co-aggregates of endogenous mouse Tau and exogenous human Tau, accompanied by loss of synapses (especially presynaptic failure) and neurons. From ~10 months onwards the mice show a prominent neuroinflammatory response as judged by activation of microglia and astrocytes. This progressive neuroinflammation becomes visible by in vivo bioluminescence imaging after crossbreeding of hTau40(AT) mice and Gfap-luciferase reporter mice. In contrast to other Tau-transgenic models and Alzheimer disease patients with reduced protein clearance, hTau40(AT) mice show a strong induction of autophagy. Although Tau-hyperphosphorylation and aggregation is also present in spinal cord and motor cortex (due to the Thy1.2 promoter), neuromotor performance is not affected. Deficits in spatial reference memory are manifest at ~16 months and are accompanied by neuronal death.
  
  
  CONCLUSIONS
  The hTau40(AT) mice mimic pathological hallmarks of tauopathies including a cognitive phenotype combined with pronounced neuroinflammation visible by bioluminescence. Thus the mice are suitable for mechanistic studies of Tau induced toxicity and in vivo validation of neuroprotective compounds.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. sydow@mpasmb.desy.de.|Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany. sydow@mpasmb.desy.de.
authors.forename: Astrid
authors.initials: A
authors.lastname: Sydow
authors.affiliation: Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Hochgräfe
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Könen
authors.affiliation: Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cadinu
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Matenia
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Petrova
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.|Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Joseph
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Frank Johannes
authors.initials: FJ
authors.lastname: Dennissen
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. mandelkow@mpasmb.desy.de.|Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany. mandelkow@mpasmb.desy.de.|CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. mandelkow@mpasmb.desy.de.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
mesh_terms: D000367:Age Factors; D000375:Aging; D000409:Alanine / Q000235:genetics; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000648:ultrastructure; D003072:Cognition Disorders / Q000209:etiology*; D016207:Cytokines / Q000378:metabolism; D049229:Dendritic Spines / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology*; D005260:Female; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011030:Pneumothorax / Q000150:complications* / Q000235:genetics*; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D013912:Threonine / Q000235:genetics; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016207:Cytokines; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D009419:Nerve Tissue Proteins; D022661:RNA, Untranslated; D016875:tau Proteins; D013912:Threonine; D000409:Alanine