Lessons from a Rare Familial Dementia: Amyloid and Beyond.

Adam Cantlon,Carlo Sala Frigerio,Dominic M Walsh

doi:10.13188/2376-922x.1000009

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.

Highlights

Dementia is a problem of immense proportions which afflicts over 36 million people [1]
The data extant are considerable and have given rise to two competing hypotheses to explain the causation of Familial British dementia (FBD) and familial Danish dementia (FDD) (Figure 2)
One hypothesis focuses on a toxic gain of function, in which mutations give rise to amyloid British (ABri) or amyloid Danish peptide (ADan) that form toxic aggregates (Figure 2A)

Summary

Introduction

Dementia is a problem of immense proportions which afflicts over 36 million people [1]. Instead DNA sequencing identified a 10 nucleotide duplication (TTTAATTTGT between codons 265 and 266), immediately prior to the normal in frame stop codon (Figure 1A) This replaces the terminal residue of BRI2 (serine) with a phenylalanine and extends the ORF generating a 277 amino acids long protein which we refer to as FDD-BRI2. Tg-FDD mice, crossed with tau transgenic mice (TauP301S) expressing mutant human tau (P301S) develop enhanced NFT pathology, tau phosphorylation and tau truncation when compared to TauP301S littermates These effects occur prior to widespread amyloid deposition indicating that soluble, non-fibril forms of ADan or expression of FDD-BRI2 augments tau pathology in these mice [64]. On the other hand BRI2 knock-in mice suggest that loss of BRI2 function

Method of detecting histological changes

Conclusion

C22 C5 or C22