BRI2 (ITM2b) Inhibits A  Deposition In Vivo

Kim, Jung-Su; Miller, Victor M.; Levites, Yona; West, Karen Jansen; Zwizinski, Craig; Moore, Brenda D.; Troendle, Fredrick J.; Bann, Maralyssa; Verbeeck, Christophe; Price, Robert W. R.; Smithson, Lisa; Sonoda, Leilani K.; Wagg, Kayleigh; Rangachari, Vijayaraghavan; Zou, Fanggeng; Younkin, Steven G.; Graff‐Radford, Neill R.; Dickson, Dennis W.; Rosenberry, Terrone L.; Golde, Todd E.

doi:10.1523/jneurosci.0891-08.2008

Cited by 109 publications

(117 citation statements)

References 31 publications

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“…However, in patients the colocalization of Aβ and ADan has been reported to be incomplete (4,12,13), as was seen in the mice. Our observations of reduced Aβ deposition in the ADanPP/APP tg mice are consistent with previous studies, showing that secreted and potentially amyloidogenic peptides, such as Aβ1-40, Bri2-23, cystatin C, and transthyretin, can inhibit Aβ pathogenesis (34)(35)(36)(37). These peptides have been reported to bind Aβ, suggesting that the formation of heterogenous structures may prevent mature amyloid fibril formation (35, 38, 39).…”

Section: Discussionsupporting

confidence: 92%

Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease

Coomaraswamy

Kilger

Wölfing

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Familial Danish dementia (FDD) is a progressive neurodegenerative disease with cerebral deposition of Dan-amyloid (ADan), neuroinflammation, and neurofibrillary tangles, hallmark characteristics remarkably similar to those in Alzheimer's disease (AD). We have generated transgenic (tg) mouse models of familial Danish dementia that exhibit the age-dependent deposition of ADan throughout the brain with associated amyloid angiopathy, microhemorrhage, neuritic dystrophy, and neuroinflammation. Tg mice are impaired in the Morris water maze and exhibit increased anxiety in the open field. When crossed with TauP301S tg mice, ADan accumulation promotes neurofibrillary lesions, in all aspects similar to the Tau lesions observed in crosses between β-amyloid (Aβ)-depositing tg mice and TauP301S tg mice. Although these observations argue for shared mechanisms of downstream pathophysiology for the sequence-unrelated ADan and Aβ peptides, the lack of codeposition of the two peptides in crosses between ADan-and Aβ-depositing mice points also to distinguishing properties of the peptides. Our results support the concept of the amyloid hypothesis for AD and related dementias, and suggest that different proteins prone to amyloid formation can drive strikingly similar pathogenic pathways in the brain.ADan | ABeta | tau | neurodegeneration | mouse model

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Section: Discussionsupporting

confidence: 92%

Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease

Coomaraswamy

Kilger

Wölfing

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Bri2 suppresses A␤ deposition in APP transgenic mice by influencing APP processing (39). Together with our results, it is tempting to speculate that the Bri2 BRICHOS domain indeed has a natural protective role against A␤ aggregation and AD.…”

Section: Discussionsupporting

confidence: 71%

BRICHOS Domains Efficiently Delay Fibrillation of Amyloid β-Peptide

Willander

Presto

Askarieh

et al. 2012

Journal of Biological Chemistry

129

160

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Background: Alzheimer disease (AD) is associated with A␤ protein misfolding and aggregation into fibrils rich in ␤-sheet structure. Results: BRICHOS domains prevent fibril formation of A␤ far below the stoichiometric ratio. Conclusion: A␤ is maintained as an unstructured monomer in the presence of BRICHOS. Significance: BRICHOS domain can have a natural protective role against A␤ aggregation, which may open new routes toward AD therapy.

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“…(J) Densitometry values showed no difference in prefibrillar oligomers between WT and Bri2 +/− mice. Average value for WT samples was arbitrarily equaled to 100. duction (11,16,(25)(26)(27)(28). Although we did not detect alterations in Aβ or toxic oligomers levels in FDD KI/+ mice, it is possible that synaptotoxic ADan and/or Aβ oligomers may augment in anatomically restricted locations and/or increase transiently during memory acquisition/consolidation.…”

Section: Discussionmentioning

confidence: 58%

Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits

Tamayev

Matsuda

Fà

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

103

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According to the prevailing "amyloid cascade hypothesis," genetic dementias such as Alzheimer's disease and familial Danish dementia (FDD) are caused by amyloid deposits that trigger tauopathy, neurodegeneration, and behavioral/cognitive alterations. To efficiently reproduce amyloid lesions, murine models of human dementias invariably use transgenic expression systems. However, recent FDD transgenic models showed that Danish amyloidosis does not cause memory defects, suggesting that other mechanisms cause Danish dementia. We studied an animal knock-in model of FDD (FDD KI/+ ) genetically congruous with human cases. FDD KI/+ mice present reduced Bri2 levels, impaired synaptic plasticity and severe hippocampal memory deficits. These animals show no cerebral lesions that are reputed characteristics of human dementia, such as tangles or amyloid plaques. Bri2 +/− mice exhibit synaptic and memory deficits similar to FDD KI/+ mice, and memory loss of FDD KI/+ mice is prevented by expression of WT BRI2, indicating that Danish dementia is caused by loss of BRI2 function. Together, the data suggest that clinical dementia in Danish patients occurs via a loss of function mechanism and not as a result of amyloidosis and tauopathy.amyloid-β precursor protein | ITM2b T he condition known as Danish dementia (FDD) is due to a dominant autosomal mutation in the BRI2/ITM2b gene (1). The BRI2 precursor (immature, imBRI2) is a type-II membrane protein that is cleaved at the C terminus by proprotein convertase to produce the mature BRI2 protein (mBRI2) and a 23aa soluble C-terminal fragment (2). FDD is caused by a 10-nucleotide duplication before the stop codon of the BRI2 gene (1). The Danish mutant protein (BRI2-ADan) generates a longer C-terminal fragment, ADan (Fig. S1A), which forms widespread amyloid angiopathy in the small blood vessels and capillaries of the cerebrum, choroid plexus, cerebellum, spinal cord, and retina (1). Neuropathological examination of patients with FDD also shows diffuse brain atrophy with a particularly severe involvement of the cerebellum, cerebral cortex and white matter, as well as the presence of very thin and almost demyelinated cranial nerves; neurofibrillary tangles are the major histological finding in the hippocampus (1).Vidal et al. have described a transgenic mouse overexpressing BRI2-ADan, which presents widespread cerebral amyloid angiopathy and parenchymal amyloid deposition of the ADan peptide (3). More recently, another FDD transgenic model with ADan deposition (called ADanPP-Tg mice) has been described (4). ADanPP-Tg mice do not show cognitive and memory defects in the first 12 mo of life despite considerable amyloid load. At an older age, ADanPP-Tg mice show deficits with the cue navigation task of the Morris water maze associated with an increase of thigmotaxis and passive floating, lower speed, less body weight, and an anxiety-related phenotype (4). Thus, although the ADan peptide is believed to cause Danish dementia, the absence of memory deficits despite massive ADan peptide produc...

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BRI2 (ITM2b) Inhibits A Deposition In Vivo

Cited by 109 publications

References 31 publications

Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease

Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease

BRICHOS Domains Efficiently Delay Fibrillation of Amyloid β-Peptide

Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits

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