title: Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease.
abstract: Familial Danish dementia (FDD) is a progressive neurodegenerative disease with cerebral deposition of Dan-amyloid (ADan), neuroinflammation, and neurofibrillary tangles, hallmark characteristics remarkably similar to those in Alzheimer's disease (AD). We have generated transgenic (tg) mouse models of familial Danish dementia that exhibit the age-dependent deposition of ADan throughout the brain with associated amyloid angiopathy, microhemorrhage, neuritic dystrophy, and neuroinflammation. Tg mice are impaired in the Morris water maze and exhibit increased anxiety in the open field. When crossed with TauP301S tg mice, ADan accumulation promotes neurofibrillary lesions, in all aspects similar to the Tau lesions observed in crosses between beta-amyloid (Abeta)-depositing tg mice and TauP301S tg mice. Although these observations argue for shared mechanisms of downstream pathophysiology for the sequence-unrelated ADan and Abeta peptides, the lack of codeposition of the two peptides in crosses between ADan- and Abeta-depositing mice points also to distinguishing properties of the peptides. Our results support the concept of the amyloid hypothesis for AD and related dementias, and suggest that different proteins prone to amyloid formation can drive strikingly similar pathogenic pathways in the brain.
authors.affiliation: Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, 72076 Tübingen, Germany. janaky.coomaraswamy@uni-tuebingen.de
authors.forename: Janaky
authors.initials: J
authors.lastname: Coomaraswamy
authors.forename: Ellen
authors.initials: E
authors.lastname: Kilger
authors.forename: Heidrun
authors.initials: H
authors.lastname: Wölfing
authors.forename: Claudia
authors.initials: C
authors.lastname: Schäfer
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Kaeser
authors.forename: Bettina M
authors.initials: BM
authors.lastname: Wegenast-Braun
authors.forename: Jasmin K
authors.initials: JK
authors.lastname: Hefendehl
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Matthew
authors.initials: M
authors.lastname: Mazzella
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Francisco
authors.initials: F
authors.lastname: Garcia-Sierra
authors.forename: David P
authors.initials: DP
authors.lastname: Wolfer
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D003704:Dementia / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D006652:Histological Techniques; D007118:Immunoassay; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009483:Neuropsychological Tests
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins
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