Lessons from a Rare Familial Dementia: Amyloid and Beyond

Abstract

Here we review the similarities between a rare inherited disorder, familial British dementia (FBD), and the most common of all late-life neurological conditions, Alzheimer's diseases (AD). We describe the symptoms, pathology and genetics of FBD, the biology of the BRI2 protein and mouse models of FBD and familial Danish dementia. In particular, we focus on the evolving recognition of the importance of protein oligomers and aberrant processing of the amyloid β-protein precursor (APP) - themes that are common to both FBD and AD. The initial discovery that FBD is phenotypically similar to AD, but associated with the deposition of an amyloid peptide (ABri) distinct from the amyloid β-protein (Aβ) led many to assume that amyloid production alone is sufficient to initiate disease and that ABri is the molecular equivalent of Aβ. Parallel with work on Aβ, studies of ABri producing animal models and in vitro ABri toxicity experiments caused a revision of the amyloid hypothesis and a focus on soluble oligomers of Aβ and ABri. Contemporaneous other studies suggested that loss of the ABri precursor protein (BRI2) may underlie the cognitive deficits in FBD. In this regard it is important to note that BRI2 has been shown to interact with and regulate the processing of APP, and that mutant BRI2 leads to altered cleavage of APP. A synthesis of these results suggests that a “two-hit mechanism” better explains FBD than earlier toxic gain of function and toxic loss of function models. The lessons learned from the study of FBD imply that the molecular pathology of AD is also likely to involve both aberrant aggregation (in AD, Aβ) and altered APP processing. With regard to FBD, we propose that the C-terminal 11 amino acid of FBD-BRI2 interfere with both the normal function of BRI2 and promotes the production of cystine cross-linked toxic ABri oligomers. In this scenario, loss of BRI2 function leads to altered APP processing in as yet underappreciated ways. Given the similarities between FBD and AD it seems likely that study of the structure of ABri oligomers and FBD-induced changes in APP metabolites will further our understanding of AD.

BRICHOS binds to a designed amyloid-forming β-protein and reduces proteasomal inhibition and aggresome formation

“…These observations suggest possible mechanistic links between the two diseases. It has been suggested that FBD and FDD are either caused by the aggregation of ABri and ADan respectively, and/or a loss-of function of mature Bri2 (Cantlon, et al, 2015b). Experimental support for both theories can be found.…”

“…The FDD mutation leads to a 10-nucleotide duplication, causing a frame shift replacing the stop codon of Bri2, extending the peptide to another 34 residue long peptide. Both ABri and ADan are 11 residues longer than the nonpathogenic Bri2 C-terminal peptide, Bri23, but the additional residues share no sequence ADan TM similarity (Cantlon, et al, 2015b). Aβ42 and Aβ4-42 have been found in both fibrillar and non-fibrillar deposits of ADan in FDD (Tomidokoro, et al, 2005), and Bri2 has been found to deposit with Aβ plaques in AD (Del Campo, et al, 2014a).…”

“…Mutations in Bri2 give rise to release of extended, 34-residue C-terminal peptides, ABri or ADan. ABri and ADan deposit in the CNS in two rare amyloid diseases, familial British dementia (FBD) and familial Danish dementia (FDD), respectively (Cantlon, et al, 2015b). After the discovery of the pathogenic FBD and FDD mutations, and Bri2 as the precursor to the ABri and ADan peptides (Vidal, et al, 1999,Vidal, et al, 2000, furin was identified as responsible for the proteolytic cleavage releasing the C-terminal peptides (Kim, et al, 1999).…”

Transthyretin and BRICHOS: The Paradox of Amyloidogenic Proteins with Anti-Amyloidogenic Activity for Aβ in the Central Nervous System

“…Processing of Bri2 by furin releases a 23-residue peptide referred to as Bri23 (corresponding to residues 244–266 of Bri2) from the C-terminal region. Mutations in Bri2 give rise to release of extended, 34-residue, C-terminal peptides, ABri, or ADan, that deposit primarily in the CNS in two rare amyloid diseases, familial British dementia (FBD) and familial Danish dementia (FDD), respectively (Cantlon et al, 2015a ). After the discovery of the pathogenic FBD and FDD mutations and Bri2 as the precursor to the ABri and ADan peptides (Vidal et al, 1999 , 2000 ), furin was identified as the major protease responsible for the proteolytic cleavage releasing the C-terminal peptides (Kim et al, 1999 ), but other proprotein-like convertases may also process Bri2, releasing C-terminal peptides (Kim et al, 1999 ; Vidal et al, 2000 ).…”

“…These observations suggest possible links between the events underlying the two diseases. It has been suggested that FBD and FDD are caused by the aggregation of ABri and ADan respectively, and/or by a loss-of function of mature Bri2 (Cantlon et al, 2015a ). Experimental support for both theories can be found.…”