Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease

被引：54

作者：

Coomaraswamy, Janaky ^{[1
,4
]}

Kilger, Ellen ^{[1
,4
]}

Woelfing, Heidrun ^{[1
,2
,4
]}

Schaefer, Claudia ^{[1
,4
]}

Kaeser, Stephan A. ^{[1
,4
]}

Wegenast-Braun, Bettina M. ^{[1
,2
,4
]}

Hefendehl, Jasmin K. ^{[1
,2
,4
]}

Wolburg, Hartwig ^{[3
]}

Mazzella, Matthew ^{[5
]}

Ghiso, Jorge ^{[6
]}

Goedert, Michel ^{[7
]}

Akiyama, Haruhiko ^{[8
]}

Garcia-Sierra, Francisco ^{[9
]}

Wolfer, David P. ^{[10
,11
,12
]}

Mathews, Paul M. ^{[5
,6
]}

Jucker, Mathias ^{[1
,4
]}

机构：

[1] Univ Tubingen, Dept Cellular Neurol, Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany

[2] Univ Tubingen, Grad Sch Cellular & Mol Neurosci, D-72076 Tubingen, Germany

[3] Univ Tubingen, Dept Pathol, D-72076 Tubingen, Germany

[4] German Ctr Neurodegenerat Dis, D-72076 Tubingen, Germany

[5] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA

[6] NYU, Sch Med, New York, NY 10016 USA

[7] MRC, Mol Biol Lab, Cambridge CB2 2QH, England

[8] Tokyo Inst Psychiat, Tokyo 1568585, Japan

[9] Natl Polytech Inst, Ctr Res & Adv Studies, Dept Cell Biol, Mexico City 07360, DF, Mexico

[10] Univ Zurich, Inst Anat, CH-8057 Zurich, Switzerland

[11] Univ Zurich, Ctr Integrat Human Physiol, CH-8057 Zurich, Switzerland

[12] Swiss Fed Inst Technol, CH-8057 Zurich, Switzerland

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 17期

关键词：

ADan; ABeta; tau; neurodegeneration; mouse model; TRANSGENIC MICE; A-BETA; PRECURSOR PROTEIN; BRITISH DEMENTIA; CYSTATIN-C; CEREBRAL AMYLOIDOSIS; TAU-PATHOLOGY; MOUSE MODELS; MUTANT FORM; BRI2; ITM2B;

D O I：

10.1073/pnas.1001056107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：7969 / 7974

页数：6