The Familial British Dementia Mutation Promotes Formation of Neurotoxic Cystine Cross-linked Amyloid Bri (ABri) Oligomers

Cantlon, Adam; Frigerio, Carlo Sala; Freir, Darragh B.; Boland, Barry; Jin, Ming; Walsh, Dominic M.

doi:10.1074/jbc.m115.652263

Cited by 12 publications

(10 citation statements)

References 54 publications

(63 reference statements)

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“…inhibits hippocampal LTP (Cantlon, et al, 2015a), similar to Aβ. The proposal that reduction in Bri2 levels causes FBD and FDD is based on the finding that Bri2 can affect AβPP processing.…”

Section: Bri2 In Familial British and Danish Dementia And Links To Aβppmentioning

confidence: 86%

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

Dolfe

Winblad

Johansson

et al. 2016

Biochemical Journal

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The BRICHOS domain is associated with proliferative, degenerative and amyloid diseases, and it has been shown to inhibit fibril formation and toxicity of the Alzheimer's disease-associated amyloid β-peptide. ProSP-C (prosurfactant protein C) BRICHOS binds to stretches of hydrophobic amino acid residues, which are unfolded or in β-strand conformation, suggesting that it may have broad anti-amyloid activity. We have studied the effect of the proSP-C BRICHOS domain on the designed amyloidogenic β-sheet proteins β17 and β23. β17 expressed in the secretory pathway of HEK (human embryonic kidney)-293 cells forms intracellular inclusions, whereas β23 is rapidly degraded. Co-expression of BRICHOS leads to a reduction in β17 inclusion size and increased levels of soluble β17 and β23. Furthermore, BRICHOS interacts with the β-proteins intracellularly, reduces their ubiquitination and decreases aggresome formation and proteasomal inhibition. Collectively, these data suggest that BRICHOS is capable of delaying the aggregation process and toxicity of amyloidogenic proteins in a generic manner.

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Section: Bri2 In Familial British and Danish Dementia And Links To Aβppmentioning

confidence: 86%

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

Dolfe

Winblad

Johansson

et al. 2016

Biochemical Journal

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“…Based on the general consensus that aggregation of Aβ is required for toxicity, we employed a partially aggregated preparation of Aβ(1–42) that contained both amyloid fibrils and Aβ monomer [ 4 , 62 ]. This preparation is referred to as 1/2 t max , because it is produced by incubating Aβ monomer for a period that yields half of the maximal level of thioflavin T. When used at concentration ≥ 10 μM, 1/2 t max can cause the compromise and death of cultured rodent and human neurons within a period of a few days [ 4 , 62 ]. Synthetic monomer Aβ (1–42) (human sequence) was obtained from rPeptide (A-1165-2).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways

et al. 2018

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MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here, we describe a neuroprotective function of miR-132, the miRNA most significantly downregulated in neurons in Alzheimer’s disease. We demonstrate that miR-132 protects primary mouse and human wild-type neurons and more vulnerable Tau-mutant neurons against amyloid β-peptide (Aβ) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF-Tau pathology and neurodegeneration, and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3β, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1880-5) contains supplementary material, which is available to authorized users.

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“…One hypothesis focuses on a toxic gain of function, in which mutations give rise to ABri or ADan that form toxic aggregates ( Figure 2A ). In vitro , aggregation studies have shown that ABri and ADan form oligomers, protofibrils and fibrils [ 51 , 53 ], while under similar conditions Bri does not readily aggregate and the assemblies Bri does form are not toxic [ 56 ]. Further, Tg-FDD and ADanPP7 mice exhibit age-dependent amyloid deposition associated with neuritic dystrophy, microglial activation, aberrant tau phosphorylation and deficits in motor control [ 61 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed we propose that etiology of FBD is best explained by both a toxic gain and loss of function. At a molecular level FBD is directly attributable to the increased ability of the cysteines within the ABri domain of FBD-BRI2 to form intermolecular cross-links that act: (i) to destabilize FBD-BRI2 and make it less prone to proteolytic maturation, and (ii) to give rise to the formation of covalently stabilized toxic ABri oligomers ( Figure 3 ) [ 56 ]. In this model reduced levels of mature BRI2 contribute to impaired synaptic plasticity, and cystine-linked ABri oligomers cause aberrant changes in tau and consequent neuronal loss.…”

Section: Discussionmentioning

confidence: 99%

“…However it is important to note that these toxicity experiments had two major drawbacks: (1) immortalized undifferentiated cell lines and not neurons were used, and (2) supra-physiological concentrations of synthetic peptide, in some instances as high as 300 μM were applied [ 52 ]. Recently we used ABri preparations with defined oxidation and aggregation state and assessed their effect on synaptic plasticity using organotypic hippocampal slices, and on the viability of dissociated hippocampal neurons [ 56 ]. This allowed us to discover that the oxidation state of ABri determined both its aggregation pathway and toxic activity.…”

Section: Abri and Adan Aggregation And Toxicitymentioning

confidence: 99%

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Lessons from a Rare Familial Dementia: Amyloid and Beyond

Cantlon¹,

Frigerio

Walsh

2015

J Parkinsons Dis Alzheimers Dis

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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.

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The Familial British Dementia Mutation Promotes Formation of Neurotoxic Cystine Cross-linked Amyloid Bri (ABri) Oligomers

Cited by 12 publications

References 54 publications

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

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

MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways

Lessons from a Rare Familial Dementia: Amyloid and Beyond

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