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Iwatsubo, Takeshi

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AMYLOID ANGIOPATHY, EARLY PLAQUES & AGING

Frangione, Blas

1 January 1990 - 31 August 2006
NATIONAL INSTITUTE ON AGING
Total Funding: $ 4,063,685

FY 2003
5R01AG008721-14
$ 456,612
FY 2002
5R01AG008721-13
$ 444,978
FY 2001
5R01AG008721-12
$ 433,687
FY 2000
2R01AG008721-11
$ 455,776
FY 1999
5R01AG008721-10
$ 267,965
FY 1998
5R01AG008721-09
$ 259,193
FY 1997
5R01AG008721-08
$ 250,753
FY 1996
5R01AG008721-07
$ 242,637
FY 1995
2R01AG008721-06
$ 234,831
FY 1994
5R01AG008721-05
$ 230,118
FY 1993
5R01AG008721-04
$ 207,713
FY 1992
5R01AG008721-03
$ 207,144
FY 1991
5R01AG008721-02
$ 187,982
FY 1990
1R01AG008721-01
$ 184,296
 
 
$ 4,063,685
Abstract

Since 1983 they have focused our efforts in the characterization of amyloid deposition in familial cerebral amyloid angiopathies of different origin and in defining their genetic defects. Hereditary cerebral hemorrhage with amyloidosis-Dutch type was the first familial form to be associated with mutations of the amyloid beta precursor protein gene. Subsequently, several genetic abnormalities in early onset familial Alzheimer's disease have been analyzed and transgenic mouse models carrying familial Alzheimer's mutants have been developed. However, neither the Dutch type nor animal models of Alzheimer's disease have clarified the relationship between amyloidogenesis and neuronal dysfunction. Vascular lesions and ischemic damage may play an important role in the pathogenesis of Alzheimer's disease since a combination of Alzheimer's disease and cerebral infarction is the second commonest type of dementia. Very recently we had the opportunity to analyze a new type of dementia - familial British dementia (FBD) - an autosomal dominant form of cerebrovascular amyloidosis with neurofibrillar degeneration leading to progressive dementia. We demonstrated that a stop codon mutation of a novel gene (BRI) localized on chromosome 13 gave rise to an elongated gene product. Degradation of the carboxyl-end of this abnormal precursor molecule releases a 34 amino acid amyloid peptide (ABri) found deposited in vascular and parenchymal plaques in patients with FBD. The principal investigators propose that ABri is the main cause of neurodegeneration and dementia in the British kindred and is an ideal model to study the relationship between amyloidogenesis, vascular pathology, and neurodegeneration. They plan: Aim I: (a) to biochemically and immunohistochemically define the composition of the amyloid deposits in vascular, perivascular, and parenchymal amyloid plaques; (b) to isolate and analyze soluble ABri species and its precursor(s) in biological fluids from FBD patients as well as in transfected cells. Dr Tjeu will also determine whether the disease is localized or systemic; (c) to precisely delineate the region(s) responsible for fibrillization via synthetic peptides of different length and composition. Aim II: to construct, develop and characterize a transgenic mouse model for FBD.

73 Resulting Publications

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