Familial Cerebral Amyloid Angiopathy With Nonneuritic Amyloid Plaque Formation

Plant, Gordon T.; Révész, Tamás; Barnard, Rita; Harding, A. E.; Gautier-Smith, P. C.

doi:10.1093/brain/113.3.721

Cited by 128 publications

(116 citation statements)

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“…Familial British dementia (FBD), 1 an autosomal dominant neurodegenerative disorder, is characterized by progressive spastic tetraparesis, cerebellar ataxia, and dementia (1). The principal pathological hallmarks of FBD include severe amyloid angiopathy, non-neuritic amyloid plaques affecting cerebellum, hippocampus, and cerebral cortex, hippocampal neurofibrillary tangles, and perivascular white matter changes.…”

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confidence: 99%

Proteolytic Processing of Familial British Dementia-associated BRI Variants

Kim

Creemers

Chu

et al. 2002

Journal of Biological Chemistry

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Different mutations in the BRI 2 gene cause rare neurodegenerative conditions, termed familial British dementia (FBD) and familial Danish dementia (FDD). The mutant genes encode BRI-L and BRI-D, the precursors of fibrillogenic ABri and ADan peptides, respectively. We previously reported that furin processes both BRI-L and its wild type counterpart, BRI, resulting in the secretion of C-terminal peptides; elevated levels of peptides were generated from BRI-L. In the present study, we show that inducible expression of ␣1-antitrypsin Portland, a furin inhibitor, inhibits the endoproteolysis of BRI and BRI-L in a dose-dependent manner. Moreover, comparison of the activities of several proprotein convertases reveals that furin is most efficient in endoproteolysis of BRI and BRI-L; PACE4, PC6A, PC6B, and LPC show much lower activities. Interestingly, LPC also exhibits enhanced cleavage of BRI-L compared with BRI. Finally, we demonstrate that BRI-D is also processed by furin and, like BRI-L, the cleavage of BRI-D is more efficient than that of BRI. Interestingly, while the ABri peptide is detected both intracellularly and in the medium, the ADan peptide accumulates predominantly in intracellular compartments. We propose that intracellular accumulation of amyloidogenic ADan or ABri peptides results in the neuronal damage leading to FDD and FBD, respectively. Familial British dementia (FBD),1 an autosomal dominant neurodegenerative disorder, is characterized by progressive spastic tetraparesis, cerebellar ataxia, and dementia (1). The principal pathological hallmarks of FBD include severe amyloid angiopathy, non-neuritic amyloid plaques affecting cerebellum, hippocampus, and cerebral cortex, hippocampal neurofibrillary tangles, and perivascular white matter changes. The genetic defect underlying FBD was recently identified (2); affected patients have a T to A transversion (TGA3 AGA) at the stop codon of the BRI 2 gene (3-5) that results in the generation of an arginine codon and a longer open reading frame that encodes a 277-amino acid protein, termed BRI-L (2). A 34-amino acid peptide, termed ABri, generated by endoproteolytic processing of this mutant precursor protein is deposited in the brains of FBD patients (2, 6). Interestingly, a different genetic defect of the BRI 2 gene was found in another rare, autosomal dominant, neurodegenerative disease, familial Danish dementia (FDD) (7). Clinical symptoms of FDD include progressive development of cataracts and hearing impairments as well as other neurological symptoms and dementia. The BRI 2 mutation in FDD is the presence of a 10-nucleotide (TTTAATTTGT) duplication between codons 265 and 266, just prior to the normal termination codon. This decamer duplication leads to the loss of serine 266 and a change in the reading frame to generate an 11-amino acid longer protein (BRI-D) that has a unique C-terminal sequence. The resulting C-terminal 34-amino acid peptide, termed ADan, is the major component of insoluble amyloid fibrils in brains of FDD patients (7). Thus, ABri and ...

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confidence: 99%

Proteolytic Processing of Familial British Dementia-associated BRI Variants

Kim

Creemers

Chu

et al. 2002

Journal of Biological Chemistry

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“…The LTP paradigm we employ takes only 90 min from the initial application of peptide until the end of the experiment and compared with most other commonly used assays of toxicity is relatively rapid. Second, loss of synapses is an early and invariant event in AD and FBD (15,16,42) and is anticipated to be preceded by changes in synaptic function. Indeed, in the case of AD it has been suggested that neuronal loss may occur as a consequence of persistent disruption of plasticity (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

“…Protein masses were acquired over two ranges: 1-10 and 10 -25 kDa, and calibration was performed using insulin (5,735 Da) and myoglobin (16,952 Da), respectively (Bruker, Billerica, MA). Spectra were summed from 2500 laser shots from an Nd:YAG laser operating at 355 nm and 200 Hz, and were acquired with an accepted signal-to-noise ratio set to Ͼ20.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, the neuropathological presentation of FDB is highly similar to that seen in Alzheimer disease (AD); indeed, even the phosphorylation sites found on neurofibrillary tangles in FBD brain are the same as those present in AD (12). These findings, together with the clinical similarities shared by FBD and AD, have promoted the notion that FBD is effectively a phenocopy of AD, with ABri the molecular equivalent of the AD-associated amyloid ␤-protein (A␤) (13)(14)(15)(16)). Yet the sequences and innate biophysical properties of ABri and A␤ are quite different.…”

Section: Familial British Dementia (Fbd)mentioning

confidence: 99%

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

Cantlon

Frigerio

Freir

et al. 2015

Journal of Biological Chemistry

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Background: Familial British dementia is a disorder similar to Alzheimer disease and is believed to be caused by the ABri peptide. Results: Cystine-linked oligomers of ABri are toxic to neurons and block long-term potentiation. Conclusion:The type and toxicity of ABri assemblies depends on cystine bond formation. Significance: ABri offers a tractable system to study the structure of disease-causing oligomers.

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“…Both conditions are distinguished by progressive dementia, spasticity and cerebellar ataxia with a neuropathology remarkably similar to that seen in AD, including amyloid deposition in the cerebral vessels, the presence of neuritic, non-neuritic and perivascular amyloid plaques, and NFT. [10][11][12][13] Amyloid deposits in FBD and FDD are made of two newly created amyloid peptides: ABri and ADan. Both peptides derive from mutant forms of the same precursor protein, BriPP, codified by a gene (BRI) located on the long arm of chromosome 13 with a primary structure that resembles a type II single-spanning transmembrane protein.…”

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confidence: 99%