Familial Danish Dementia

Yasushi Tomidokoro, Tammaryn Lashley, Agueda Rostagno, Thomas A. Neubert, Marie Bojsen-Møller, Hans Braendgaard, Gordon Plant, Janice Holton, Blas Frangione, Tamas Révész, Jorge Ghiso
2005 Journal of Biological Chemistry  
Familial Danish dementia is an early onset autosomal dominant neurodegenerative disorder linked to a genetic defect in the BRI2 gene and clinically characterized by dementia and ataxia. Cerebral amyloid and preamyloid deposits of two unrelated molecules (Danish amyloid (ADan) and ␤-amyloid (A␤)), the absence of compact plaques, and neurofibrillary degeneration indistinguishable from that observed in Alzheimer disease (AD) are the main neuropathological features of the disease. Biochemical
more » ... is of extracted amyloid and preamyloid species indicates that as the solubility of the deposits decreases, the heterogeneity and complexity of the extracted peptides exponentially increase. Nonfibrillar deposits were mainly composed of intact ADan-(1-34) and its N-terminally modified (pyroglutamate) counterpart together with A␤-(1-42) and A␤-(4-42) in ϳ1:1 mixture. The post-translational modification, glutamate to pyroglutamate, was not present in soluble circulating ADan. In the amyloid fractions, ADan was heavily oligomerized and highly heterogeneous at the N and C terminus, and, when intact, its N terminus was post-translationally modified (pyroglutamate), whereas A␤ was mainly A␤-(4-42). In all cases, the presence of A␤-(X-40) was negligible, a surprising finding in view of the prevalence of A␤40 in vascular deposits observed in sporadic and familial AD, Down syndrome, and normal aging. Whether the presence of the two amyloid subunits is imperative for the disease phenotype or just reflects a conformational mimicry remains to be elucidated; nonetheless, a specific interaction between ADan oligomers and A␤ molecules was demonstrated in vitro by ligand blot analysis using synthetic peptides. Theabsenceofcompactplaquesinthepresenceofextensiveneurofibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia. Familial Danish dementia (FDD), 2 originally described by Strömgren et al. in 1970 (1) as heredopathia opthalmo-oto-encephalica, is an early onset autosomal dominant neurodegenerative disorder characterized by cataracts, deafness, progressive ataxia, and dementia (1, 2). Retinal neovascularizations eventually resulting in vitreous hemorrhage and neovascular glaucoma may also be present (3) . Cataracts occurring around 20 years of age seem to be the first manifestation of the disease. Hearing loss develops 10 -20 years later, and cerebellar ataxia occurs, in general, shortly after the age of 40. Paranoid psychosis usually appears after the age of 50, evolving to cognitive impairment and dementia in the majority of the cases. Most patients die in their fifth or sixth decade of life. Neuropathologically, FDD shares several features with Alzheimer disease (AD), among them widespread cerebrovascular amyloidosis, parenchymal amyloid and preamyloid lesions, and neurofibrillary degeneration (4, 5). Vascular and perivascular amyloid, parenchymal preamyloid lesions, and scarce neuritic plaques in the hippocampus are mainly composed of ADan peptides (4). ADan deposits co-localize with dystrophic neurites surrounding the plaques and with neurofibrillary tangles immunoreactive with hyperphosphorylated tau antibodies. As judged by their paired helical filament ultrastructure, their reactivity in immunohistochemical analysis, and their hyperphosphorylated tau pattern in Western blot analysis, these tangles are strikingly similar (if not identical) to those present in AD (5) . Surprisingly, a detailed anti-A␤ immunohistochemical survey of different brain areas from all available FDD autopsy cases (three family members from different generations, including the case analyzed in the present study (5)) unequivocally identified A␤ co-deposited with ADan mainly in vascular and perivascular amyloid lesions, although on a smaller scale the co-deposition was also observed in parenchymal preamyloid deposits (5). The fact that A␤ co-deposition was a constant feature of all three FDD cases available argues against a coincidental nonspecific interaction between two hydrophobic peptides. FDD patients are carriers of a genetic defect in the coding region of the BRI2 gene located in the long arm of chromosome 13. The wild type BRI2 gene (also known as ITM2B) encodes a 266-residue type II singlespanning transmembrane protein (BRI2) (6 -8), which under normal conditions is proteolytically processed by a furin-like protease that produces a single cleavage between Arg 243 and Glu 244 , releasing a C-terminal 23-residue peptide (9). In patients affected with FDD, a decamer duplication insertion (TTTAATTTGT) between codons 265 and 266 in the BRI2 gene 3Ј (just one codon before the normal stop codon 267) produces a frameshift that eliminates the stop signal and generates a longer than normal precursor, namely ADanPP. Furin-like proteolytic processing of ADanPP at the same Arg 243 -Glu 244 peptide bond results in the release of a 34-amino acid-long C-terminal peptide ADan, which *
doi:10.1074/jbc.m504038200 pmid:16091362 fatcat:4xq4zll36jhgtgib6wovfkz5pu