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P1–072: Transgenic mouse models of familial British and Danish dementias
Author(s) -
Coomaraswamy Janaky,
Herzig Martin C.,
Kaeser Stephan A.,
Ghiso Jorge,
Jucker Mathias
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.447
Subject(s) - genetically modified mouse , biology , amyloid precursor protein , pathogenesis , point mutation , bace1 as , mutation , transversion , transgene , pathology , alzheimer's disease , amyloid (mycology) , genetics , cerebral amyloid angiopathy , dementia , gene , microbiology and biotechnology , medicine , disease , immunology
Background: The identification of the BRI2 gene, due to its relation to Familial British Dementia (FBD) and Familial Danish Dementia (FDD), has provided a new avenue to study the amyloid hypothesis, supporting the notion that the accumulation of amyloid is critical to the pathogenesis of neurodegenerative disease. Mutations of the BRI2 gene, a T-A transversion in FBD and ten nucleotide duplication in FDD, cause continued reading or a frame-shift at the stop codon resulting in BRI2 elongations. The proteolytic C-terminal fragments generated by normal processing of the elongated precursors accumulate in the form of vascular amyloid and hippocampal plaques, coinciding with tangles in both diseases. Objective: Since the identification of mutations in BRI2 causing FBD (1999) and FDD (2000) an animal model for either disease has remained elusive. Thus, it was our objective to create transgenic mice that recapitulate the pathogenesis seen in patients. Methods: Mutations for FBD and FDD were created using point and insertional mutagenesis in cDNA encoding for the wildtype BRI2 protein. Transgenic mice were produced on a C57BL/6J background expressing either transgene under the control of the SHaPrP promoter. Initial analyses have been perfomed on our Danish mice using histological and biochemical methods. Results: Initial results demonstrate that the Danish transgenic mice accumulate amyloid predominantly in the leptomeningeal vessels beginning as early as 2.5 months of age. This amyloid accumulation progresses further in the form of cerebral amyloid angiopathy (CAA) and parenchymal plaques as the mice age. Furthermore, the Danish amyloid deposition observed is immunoreactive with an antibody specific for the C-terminal of the Danish protein as well as thioflavin S positive. Conclusions: This new transgenic mouse model of cerebral amyloidosis provides a new tool in the quest for a better understanding of the role of amyloid, particularly in CAA. This model may be beneficial not only to study mechanistic insights into FBD and FDD but also into the pathophysiology of Alzheimer’s disease and other aggregation proteopathies.