Regional Distribution of Amyloid-Bri Deposition and Its Association with Neurofibrillary Degeneration in Familial British Dementia

Holton, Janice L.; Ghiso, Jorge; Lashley, Tammaryn; Rostagno, Agueda; Guérin, Christopher J.; Gibb, G M; Houlden, Henry; Ayling, H; Martinian, Lillian; Anderton, Brian H.; Wood, Nicholas W.; Vidal, Rubén; Plant, Gordon T.; Frangione, Blas; Révész, Tamás

doi:10.1016/s0002-9440(10)63993-4

Cited by 129 publications

(120 citation statements)

References 44 publications

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“…The increase of total Tau leads to higher levels of its protein levels, a condition that favors phosphorylation and aggregation, as demonstrated with mutant Tau, when unable to bind tubulin (Holton et al ., 2001; Bunker et al ., 2006). We observed that Aβ monomers, in parallel with an increase of Tau protein levels, impair proteasomal degradation.…”

Section: Discussionmentioning

confidence: 99%

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Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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SummaryThe mechanistic relationship between amyloid β1‐42 (Aβ1‐42) and the alteration of Tau protein are debated. We investigated the effect of Aβ1‐42 monomers and oligomers on Tau, using mice expressing wild‐type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aβ1‐42, mice were sacrificed after 3 h or 4 days. The short‐lasting treatment with Aβ monomers, but not oligomers, showed a conformational PHF‐like change of Tau, together with hyperphosphorylation. The same treatment induced increase in concentration of GSK3 and MAP kinases. The inhibition of the kinases rescued the Tau changes. Aβ monomers increased the levels of total Tau, through the inhibition of proteasomal degradation. Aβ oligomers reproduced all the aforementioned alterations only after 4 days of treatment. It is known that Aβ1‐42 monomers foster synaptic activity. Our results suggest that Aβ monomers physiologically favor Tau activity and dendritic sprouting, whereas their excess causes Tau pathology. Moreover, our study indicates that anti‐Aβ therapies should be targeted to Aβ1‐42 monomers too.

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Section: Discussionmentioning

confidence: 99%

“…The third hypothesis is supported by the occurrence of Tau pathology in different types of cerebral amyloidosis (Holton et al ., 2001; Giaccone et al ., 2008). …”

Section: Introductionmentioning

confidence: 99%

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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“…This early onset disorder, clinically characterized by progressive dementia, cerebellar ataxia, and spastic paraparesis, was first described by Worster-Drought et al (1933) as a familial presenile dementia with spastic paralysis (10 -13). The neuropathology of FBD is remarkably similar to that of FDD and AD, particularly in regard to the presence of neurofibrillary tangles ultrastructurally composed of classical paired helical filaments (14,15). As in FDD, the stop to Arg point mutation in FBD also eliminates the BRI2 stop codon and generates a longer than normal precursor ABriPP.…”

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confidence: 86%

Familial Danish Dementia

Tomidokoro

Lashley²,

Rostagno

et al. 2005

Journal of Biological Chemistry

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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 ␤-amyloid (A␤)), 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 ADan-(1-34) and its N-terminally modified (pyroglutamate) counterpart together with A␤-(1-42) and A␤-(4-42) in ϳ1:1 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␤ was mainly A␤-(4-42). In all cases, the presence of A␤-(X-40) was negligible, a surprising finding in view of the prevalence of A␤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␤ molecules was demonstrated in vitro by ligand blot analysis using synthetic peptides. Theabsenceofcompactplaquesinthepresenceofextensiveneurofibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia.

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“…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).…”

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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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Regional Distribution of Amyloid-Bri Deposition and Its Association with Neurofibrillary Degeneration in Familial British Dementia

Cited by 129 publications

References 44 publications

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

Familial Danish Dementia

Proteolytic Processing of Familial British Dementia-associated BRI Variants

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