Faculty Bibliography

Gerstmann-Straussler-Scheinker disease (GSS) is a cerebral amyloidosis associated with mutations in the prion protein (PrP) gene (PRNP). The aim of this study was to characterize amyloid peptides purified from brain tissue of a patient with the A117V mutation who was Met/Val heterozygous at codon 129, Val(129) being in coupling phase with mutant Val117. The major peptide extracted from amyloid fibrils was a approximately 7-kDa PrP fragment. Sequence analysis and mass spectrometry showed that this fragment had ragged N and C termini, starting mainly at Gly88 and Gly90 and ending with Arg148, Glu152, or Asn153. Only Val was present at positions 117 and 129, indicating that the amyloid protein originated from mutant PrP molecules. In addition to the approximately 7-kDa peptides, the amyloid fraction contained N- and C-terminal PrP fragments corresponding to residues 23-41, 191-205, and 217-228. Fibrillogenesis in vitro with synthetic peptides corresponding to PrP fragments extracted from brain tissue showed that peptide PrP-(85-148) readily assembled into amyloid fibrils. Peptide PrP-(191-205) also formed fibrillary structures although with different morphology, whereas peptides PrP-(23-41) and PrP-(217-228) did not. These findings suggest that the processing of mutant PrP isoforms associated with Gerstmann-Straussler-Scheinker disease may occur extracellularly. It is conceivable that full-length PrP and/or large PrP peptides are deposited in the extracellular compartment, partially degraded by proteases and further digested by tissue endopeptidases, originating a approximately 7-kDa protease-resistant core that is similar in patients with different mutations. Furthermore, the present data suggest that C-terminal fragments of PrP may participate in amyloid formation

Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in Alzheimer's disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain

Familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the CNS and neurodegeneration. Amyloids ABri and ADan are C-terminal degradation products of the same precursor BriPP codified by the chromosome 13 BRI2 gene bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide insertion before the stop codon in FDD. Both de novo created amyloid peptides are 34 amino acids long, share 100% identity of the first 22 residues and pyroglutamate at their N-terminus. Neuritic components and NFTs containing PHF co-localize with the amyloid deposits in both disorders and the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in AD. To explore the role of inflammatory factors in these familial disorders, complement activation was assessed via immunohistochemistry, hemolytic assays and ELISA. Components and activation products (i.e. C1q, iC3b, C3d, C4d, C5b-9) were found to co-localize with plaques and vascular deposits in both diseases, suggesting in situ activation. ABri and ADan synthetic peptides activated the classical pathway in vitro and resulted in the formation of the activation products iC3b, C4d and SC5b-9 at levels comparable to those generated by Abeta42. The ability of ABri and ADan to trigger the complement cascade in vitro together with the presence of complement proteins and activation products as integral components of parenchymal and vascular amyloid deposits suggest that, as indicated in AD, the complement system may contribute to the mechanism of neurodegeneration leading to dementia

The term cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the walls of leptomeningeal and cortical arteries, arterioles and, although less frequently in capillaries and veins. It is commonly associated with Alzheimers disease, Down's syndrome and normal aging, as well as with a variety of familial conditions related to stroke and/or dementia: hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-I), various inherited disorders linked to Abeta mutants (including the Dutch variant of HCHWA), and the recently described chromosome 13 familial dementia in British and Danish kindreds. This review focuses on four different types of hereditary CAA, emphasizing the notion that CAA is not only related to stroke but also to neurodegeneration and dementia of the Alzheimer's type