• Open Access

Cerebral Amyloid Angiopathy and Parenchymal Amyloid Deposition in Transgenic Mice Expressing the Danish Mutant Form of Human BRI2

Authors

  • Ruben Vidal,

    1. Department of Pathology and Laboratory Medicine, the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana.
    Search for more papers by this author
  • Ana G. Barbeito,

    1. Department of Pathology and Laboratory Medicine, the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana.
    Search for more papers by this author
  • Leticia Miravalle,

    1. Department of Pathology and Laboratory Medicine, the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana.
    Search for more papers by this author
  • Bernardino Ghetti

    1. Department of Pathology and Laboratory Medicine, the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana.
    Search for more papers by this author

  • Reuse of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

Ruben Vidal, M.S., Ph.D., Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive MSB A136, Indianapolis, IN 46202 (E-mail: rvidal@iupui.edu)

Abstract

Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease clinically characterized by the presence of cataracts, hearing impairment, cerebellar ataxia and dementia. Neuropathologically, FDD is characterized by the presence of widespread cerebral amyloid angiopathy (CAA), parenchymal amyloid deposition and neurofibrillary tangles. FDD is caused by a 10-nucleotide duplication-insertion in the BRI2 gene that generates a larger-than-normal precursor protein, of which the Danish amyloid subunit (ADan) comprises the last 34 amino acids. Here, we describe a transgenic mouse model for FDD (Tg-FDD) in which the mouse Prnp (prion protein) promoter drives the expression of the Danish mutant form of human BRI2 . The main neuropathological findings in Tg-FDD mice are the presence of widespread CAA and parenchymal deposition of ADan. In addition, we observe the presence of amyloid-associated gliosis, an inflammatory response and deposition of oligomeric ADan. As the animals aged, they showed abnormal grooming behavior, an arched back, and walked with a wide-based gait and shorter steps. This mouse model may give insights on the pathogenesis of FDD and will prove useful for the development of therapeutics. Moreover, the study of Tg-FDD mice may offer new insights into the role of amyloid in neurodegeneration in other disorders, including Alzheimer disease.

Ancillary