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.
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