Familial Danish Dementia

Abstract

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 analysis 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.

Increased AβPP Processing in Familial Danish Dementia Patients

“…The abundance and solubility of Aβ peptides are critical determinants of amyloidosis in Alzheimer’s disease (AD). Notably, Aβ 42 co-deposits with ADan in FDD cases [24] and this co-localization in vivo may be triggered by interactions between ADan and Aβ peptides [25] in addition to an increase in the production of Aβ peptides. Hence, we compared levels of total soluble and insoluble Aβ 40 and Aβ 42 in the FDD versus the age-matched normal aging brain and the two AD samples using a sandwich enzyme-linked immuno assay (ELISA).…”

Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Maturation Machinery

“…17,47,48 The isolation and characterization of QC isoenzymes give implications for the development of selective inhibitors in order to prevent unwanted side effects.…”

Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease

“…Total Aβ was immunoprecipitated from cortical extracts and analyzed by western blot and MALDI-TOF MS as previously described (Tomidokoro, et al, 2005). Briefly, 50μl of Dynal M-280 Dynabeads (Invitrogen, Carlsbad, CA) coated with sheep anti-mouse antibodies were incubated for 24 hours at 4°C with monoclonal antibodies 4G8 and 6E10, each at a concentration of 60μg/ml (3μg of each antibody/50μl beads) while rotating end-over-end.…”