In a study published in the Proceedings of the National Academy of Sciences (PNAS) USA, researchers in the Department of Cellular Neurology at the Hertie- Institute for Clinical Brain Research (University of Tübingen, Germany) succeeded to develop a mouse model for the rare but fatal Familial Danish Dementia. The transgenic model recapitulates many features of the human disease and proves to be valuable for further research into the disease and for the development of treatment strategies. Although this is an achievement in itself, the authors recognize the implications of their results in relation to Alzheimer’s Disease – namely that it is the misfolding of proteins into amyloid structures in the brain that leads to neuronal dysfunction and dementia.
Familial Danish dementia (FDD) is a rare familial disorder with an onset before the age of 30. In some patients visual symptoms and perceptive hearing loss is followed by cerebellar ataxia. The more obvious progressive dementia symptoms occur later and patients typically die between age of 40 and 60.
The cause for the disease is a defect in the BRI2 gene, which results in the misfolding and accumulation of a misfolded protein in the brains of FDD patients. The accumulated misfolded protein has a characteristic three-dimensional structure, a so-called amyloid structure.
The deposition of proteins with amyloid structures is not only a characteristic of FDD but is also seen in Alzheimer’s Disease (AD) and various cerebral amyloid angiopathies (CAA). The accumulation of amyloid around the walls of blood vessels in the brain is the cause for the hemorrhagic strokes in CAA and is believed to play a central role in AD. Most of the current AD therapeutic trials target the formation and deposition of amyloidogenic proteins in the brains of AD patients.
Janaky Coomaraswamy and colleagues in the laboratory of Mathias Jucker at the Hertie-Institute have now developed a mouse model for FDD and show that the amyloid in FDD (the Danish-amyloid) and the amyloid in AD (the Beta-amyloid) both induce very similar neurodegenerative, neuroinflammatory, and vascular changes. Both Danish-amyloid and Beta-amyloid also induce so-called neurofibrillary tangles, another hallmark lesion of FDD and AD.
The study suggests common disease mechanisms for FDD and AD. Moreover, results suggest that therapies targeting the amyloid structure of the misfolded proteins may also be valuable treatments for both FDD and AD. With this new mouse model in hand, the scientists at the Hertie-Institute are now in a position to test such hypotheses and to develop a therapy for the rare but devastating FDD.
Title of the original publication:
Modeling Familial Danish Dementia in mice supports the concept of the amyloid hypothesis of Alzheimer’s disease.
Coomaraswamy J, Kilger E, Wölfing H, Schäfer S, Kaeser SA, Wegenast-Braun BM, Hefendehl JK, Wolburg H, Mazzella M, Ghiso J, Goedert M, Akiyama H, Garcia-Sierra F, Wolfer DP, Mathews PM, Jucker M (2010).
Proceedings of the National Academy of Sciences (PNAS) published ahead of print April 12, 2010, doi:10.1073/pnas.1001056107
Universitätsklinikum Tübingen, Zentrum für Neurologie
Hertie-Institut für klinische Hirnforschung(HIH)
Partnerstandort Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
Professor Dr. Mathias Jucker
Hertie-Institut für klinische Hirnforschung (HIH)
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