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Amyloidogenesis in familial British dementia is associated with a genetic defect on chromosome 13
1Department of Pathology, New York University School of Medicine, 550 First Avenue, Room TH-432, New York, NY 10016, USA. ghisoj01@popmail.med.nyu.edu
Abstract:
Familial British dementia (FBD) is a disorder characterized by the presence of amyloid deposits in cerebral blood vessels and brain parenchyma coexisting with neurofibrillary tangles in limbic areas. The amyloid subunit (ABri) is a 4 kDa fragment of a 266 amino acid type II single-spanning transmembrane precursor protein encoded by the BRI gene located on chromosome 13. In FBD patients, a single base substitution at the stop codon of this gene generates a larger 277-residue precursor (ABriPP-277). Proteolytic processing by a furin-like enzyme at the C-terminus of the elongated precursor generates the 34 amino acid ABri that undergoes rapid aggregation and fibrillization. ABri is structually unrelated to all known amyloids including A beta, the main component of the amyloid lesions in Alzheimer's disease (AD), indicating that cerebral deposition of amyloid molecules other than A beta can trigger similar neuropathological changes leading to neuronal loss and dementia. These data support the concept that amyloid deposition in the vascular wall and brain parenchyma is of primary importance in the initiation of neurogeneration.
Insights
Familial British dementia (FBD) involves amyloid deposits and neurofibrillary tangles. A unique amyloid subunit (ABri), unrelated to Alzheimer's disease A beta, causes FBD by triggering neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Familial British dementia (FBD) is characterized by cerebral amyloid deposits and neurofibrillary tangles.
- The amyloid subunit in FBD, ABri, originates from the BRI gene on chromosome 13.
Purpose of the Study:
- To investigate the molecular basis of ABri formation in FBD.
- To understand the role of ABri in FBD pathogenesis and its distinction from Alzheimer's disease.
Main Methods:
- Genetic analysis of the BRI gene in FBD patients.
- Biochemical characterization of the ABri precursor protein (ABriPP-277).
- Study of ABri processing and aggregation.
Main Results:
- A single base substitution in the BRI gene generates an elongated precursor, ABriPP-277.
- Proteolytic processing yields the 34-amino acid ABri, which rapidly aggregates.
- ABri is structurally distinct from the A beta amyloid found in Alzheimer's disease.
Conclusions:
- Amyloid deposition, even by non-A beta molecules like ABri, can initiate neurodegeneration and dementia.
- Vascular and parenchymal amyloid deposition is crucial for neurodegeneration in FBD.
- FBD provides insight into the primary role of amyloid in initiating neurodegenerative processes.