UCL Discovery

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 beta-amyloid(A beta)), 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 A Dan-(1-34) and its N-terminally modified ( pyroglutamate) counterpart together with A beta- ( 1 - 42) and A beta-( 4 - 42) in similar to 1: 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 beta was mainly A beta- ( 4 - 42). In all cases, the presence of A beta-(X-40) was negligible, a surprising finding in view of the prevalence of A beta 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 beta molecules was demonstrated in vitro by ligand blot analysis using synthetic peptides. The absence of compact plaques in the presence of extensive neurofibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia.