Cerebral amyloid angiopathy and parenchymal amyloid deposition in transgenic mice expressing the Danish mutant form of human BRI2.
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 BRI(2) 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 BRI(2). 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.
Vidal
Ruben
R
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. rvidal@iupui.edu
Barbeito
Ana G
AG
Miravalle
Leticia
L
Ghetti
Bernardino
B
D048868:Adaptor Proteins, Signal Transducing; D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003704:Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003718:Denmark; D004195:Disease Models, Animal; D015870:Gene Expression; D006120:Grooming / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D016133:Polymerase Chain Reaction; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016138:Walking / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse