Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 17, Pages 7969-7974Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1001056107
Keywords
ADan; ABeta; tau; neurodegeneration; mouse model
Categories
Funding
- Carl-Zeiss Foundation
- Hertie-Foundation
- German Research Foundation [JU 655/3-1]
- German National Genome Network (NGFNPlus)
- Competence Network on Degenerative Dementias [BMBF-01GI0705]
- Consejo Nacional de Ciencia y Tecnologia-Mexico [59651]
- National Center of Competence in Research Neural Plasticity and Repair
- MRC [MC_U105184291] Funding Source: UKRI
- Medical Research Council [MC_U105184291] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [21591536] Funding Source: KAKEN
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Familial Danish dementia (FDD) is a progressive neurodegenerative disease with cerebral deposition of Dan-amyloid (ADan), neuro-inflammation, 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 (A beta)-depositing tg mice and TauP301S tg mice. Although these observations argue for shared mechanisms of downstream pathophysiology for the sequence-unrelated ADan and A beta peptides, the lack of codeposition of the two peptides in crosses between ADan- and A beta-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.
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