Bri1 gene-related dementias; A morphological and biochemical study.

Aspects of the neurodegenerative mechanism in AD remain unknown therefore studies on alternative models of cerebral amyloidosis, such as familial British dementia (FBD) and familial Danish dementia (FDD) may contribute to a better understanding of the neurodegenerative process. FBD and FDD are neurodegenerative disorders caused by mutations in the BRI2 gene. Both mutations cause elongation of the precursor proteins, the furin-like cleavage of which results in the formation of amyloidogenic peptides, ABri in FBD and ADan in FDD. Extensive morphological examinations of FBD and FDD were undertaken using antibodies recognising ABri and ADan, establishing a regional distribution of CNS peptide deposits in either amyloid or pre-amyloid configuration in both diseases, including cerebral amyloid angiopathy (CAA) formation. Amyloid associated proteins (AAP) are able to modify Afi aggregation and are implicated in AD pathogenesis. Establishing whether AAPs are implicated in the pathogenesis of other cerebral amyloidoses, AAP deposition was investigated and found associated with ABri and ADan amyloid and preamyloid parenchymal lesions. Inflammatory mechanisms, including activation of the complement pathways, initiated by AJ3 deposition strongly are implicated in AD pathogenesis. The presence of the complement pathways were shown in FBD and FDD, highlighting the importance of chronic inflammation in the neurodegenerative diseases. Biochemical analysis of extracted ABri and ADan species indicates that as solubility of the deposits decrease heterogeneity and complexity of extracted peptides increases, including post-translational modification of glutamate to pyroglutamate. The production and cellular origin of the precursor proteins and the localisation of fiirin expression were investigated. Evidence is presented that BRI2 mRNA and furin are found in neurons and glia, suggesting that cleavage of the wild type and mutated precursor proteins can take place in these cells. The absence of BRI2 mRNA in cerebrovascular cells indirectly supports the drainage hypothesis of CAA