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 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.

[1]  E. Kremmer,et al.  Regulated Intramembrane Proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b* , 2008, Journal of Biological Chemistry.

[2]  M. Jucker,et al.  P1-072 Transgenic mouse models of familial British and Danish dementias , 2006, Alzheimer's & Dementia.

[3]  D. Wilcock,et al.  Dynamic Complexity of the Microglial Activation Response in Transgenic Models of Amyloid Deposition: Implications for Alzheimer Therapeutics , 2005, Journal of neuropathology and experimental neurology.

[4]  Irene Otte-Höller,et al.  Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. , 2005, The American journal of pathology.

[5]  Judianne Davis,et al.  Reducing Cerebral Microvascular Amyloid-β Protein Deposition Diminishes Regional Neuroinflammation in Vasculotropic Mutant Amyloid Precursor Protein Transgenic Mice , 2005, The Journal of Neuroscience.

[6]  J. Hardy,et al.  Aβ42 Is Essential for Parenchymal and Vascular Amyloid Deposition in Mice , 2005, Neuron.

[7]  Brian J Bacskai,et al.  Progression of Cerebral Amyloid Angiopathy in Transgenic Mouse Models of Alzheimer Disease , 2005, Journal of neuropathology and experimental neurology.

[8]  George Perry.  Faculty Opinions recommendation of Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. , 2004 .

[9]  B. Ghetti,et al.  Neurodegeneration Caused by Proteins with an Aberrant Carboxyl‐Terminus , 2004, Journal of neuropathology and experimental neurology.

[10]  J. Krakauer,et al.  Reversible leukoencephalopathy associated with cerebral amyloid angiopathy , 2004, Neurology.

[11]  E. Levy,et al.  Axonal transport of British and Danish amyloid peptides via secretory vesicles , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  J. Baron,et al.  Rapidly reversible dementia in cerebral amyloid inflammatory vasculopathy , 2004, European journal of neurology.

[13]  V. Lelyveld,et al.  Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia , 2003, Journal of neurochemistry.

[14]  M. Verbeek,et al.  Pathogenesis of cerebral amyloid angiopathy , 2003, Brain Research Reviews.

[15]  Carl W. Cotman,et al.  Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis , 2003, Science.

[16]  Hirotaka Yoshida,et al.  Abundant Tau Filaments and Nonapoptotic Neurodegeneration in Transgenic Mice Expressing Human P301S Tau Protein , 2002, The Journal of Neuroscience.

[17]  G. Plant,et al.  Complement Activation in Chromosome 13 Dementias , 2002, The Journal of Biological Chemistry.

[18]  G. Plant,et al.  Familial Danish Dementia: A Novel Form of Cerebral Amyloidosis Associated with Deposition of Both Amyloid‐Dan and Amyloid‐Beta , 2002, Journal of neuropathology and experimental neurology.

[19]  James P. O'Callaghan,et al.  Time Course of the Development of Alzheimer-like Pathology in the Doubly Transgenic PS1+APP Mouse , 2002, Experimental Neurology.

[20]  S. Sisodia,et al.  Proteolytic Processing of Familial British Dementia-associated BRI Variants , 2002, The Journal of Biological Chemistry.

[21]  M. Moskowitz,et al.  Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. , 2001, The American journal of pathology.

[22]  L. Martinian,et al.  Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia. , 2001, The American journal of pathology.

[23]  I. Tesseur,et al.  Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons , 2000, Neurobiology of Aging.

[24]  T Bek,et al.  A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[25]  D. Steiner,et al.  Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia , 1999, Nature Neuroscience.

[26]  Agueda Rostagno,et al.  A stop-codon mutation in the BRI gene associated with familial British dementia , 1999, Nature.

[27]  Yu-Min Kuo,et al.  Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. , 1998, The American journal of pathology.

[28]  K Nakayama,et al.  Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. , 1997, The Biochemical journal.

[29]  D L Price,et al.  A vector for expressing foreign genes in the brains and hearts of transgenic mice. , 1996, Genetic analysis : biomolecular engineering.

[30]  E. van Marck,et al.  Isolation of Markers for Chondro-osteogenic Differentiation Using cDNA Library Subtraction , 1996, The Journal of Biological Chemistry.

[31]  B. Pollo,et al.  ßPP Participates in PrP-Amyloid Plaques of Gerstmann-Sträussler-Scheinker Disease, Indiana Kindred , 1993, Journal of neuropathology and experimental neurology.

[32]  H. Vinters,et al.  Immunohistochemical study of cerebral amyloid angiopathy. III. Widespread alzheimer A4 peptide in cerebral microvessel walls colocalizes with gamma trace in patients with leukoencephalopathy , 1990, Annals of neurology.

[33]  H. Vinters.  Cerebral amyloid angiopathy. A critical review. , 1987, Stroke.

[34]  L. Wood,et al.  About the Authors , 1980, European Respiratory Journal.

[35]  E. Strömgren,et al.  CATARACT, DEAFNESS, CEREBELLAR ATAXIA, PSYCHOSIS AND DEMENTIA—A NEW SYNDROME , 1970, Acta neurologica Scandinavica.

[36]  J. Rogers,et al.  Neuroinflammation in Alzheimer's disease and Parkinson's disease: are microglia pathogenic in either disorder? , 2007, International review of neurobiology.

[37]  C. Janus,et al.  Plaques, Tangles, and Memory Loss in Mouse Models of Neurodegeneration , 2007, Behavior genetics.

[38]  R O Weller,et al.  Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. , 1998, The American journal of pathology.