Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease.
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.
Coomaraswamy
Janaky
J
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
Kilger
Ellen
E
Wölfing
Heidrun
H
Schäfer
Claudia
C
Kaeser
Stephan A
SA
Wegenast-Braun
Bettina M
BM
Hefendehl
Jasmin K
JK
Wolburg
Hartwig
H
Mazzella
Matthew
M
Ghiso
Jorge
J
Goedert
Michel
M
Akiyama
Haruhiko
H
Garcia-Sierra
Francisco
F
Wolfer
David P
DP
Mathews
Paul M
PM
Jucker
Mathias
M
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
D048868:Adaptor Proteins, Signal Transducing; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins
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