Verification of the Intermolecular Parallel β-Sheet in E22K-Aβ42 Aggregates by Solid-State NMR Using Rotational Resonance: Implications for the Supramolecular Arrangement of the Toxic Conformer of Aβ42

Masuda, Yuichi; Nakanishi, Azusa; Ohashi, Rikiya; Takegoshi, K.; Shimizu, Takahiko; Shirasawa, Takuji; Irie, Kazuhiro

doi:10.1271/bbb.80250

Cited by 18 publications

(11 citation statements)

References 20 publications

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“…The amyloid-β 1-40 aggregates produced in the thioflavin-T assay were examined by electron microscope [43]. After 6-hour incubation at 37 °C, the samples were centrifuged at 16,000 × g at 4 °C for 90 min.…”

Section: Methodsmentioning

confidence: 99%

Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy

Saitô

Yamamoto

Maki

et al. 2017

acta neuropathol commun

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Cerebral amyloid angiopathy (CAA) induces various forms of cerebral infarcts and hemorrhages from vascular amyloid-β accumulation, resulting in acceleration of cognitive impairment, which is currently untreatable. Soluble amyloid-β protein likely impairs cerebrovascular integrity as well as cognitive function in early stage Alzheimer’s disease. Taxifolin, a flavonol with strong anti-oxidative and anti-glycation activities, has been reported to disassemble amyloid-β in vitro but the in vivo relevance remains unknown. Here, we investigated whether taxifolin has therapeutic potential in attenuating CAA, hypothesizing that inhibiting amyloid-β assembly may facilitate its clearance through several elimination pathways. Vehicle- or taxifolin-treated Tg-SwDI mice (commonly used to model CAA) were used in this investigation. Cognitive and cerebrovascular function, as well as the solubility and oligomerization of brain amyloid-β proteins, were investigated. Spatial reference memory was assessed by water maze test. Cerebral blood flow was measured with laser speckle flowmetry and cerebrovascular reactivity evaluated by monitoring cerebral blood flow changes in response to hypercapnia. Significantly reduced cerebrovascular pan-amyloid-β and amyloid-β1-40 accumulation was found in taxifolin-treated Tg-SwDI mice compared to vehicle-treated counterparts (n = 5). Spatial reference memory was severely impaired in vehicle-treated Tg-SwDI mice but normalized after taxifolin treatment, with scoring similar to wild type mice (n = 10–17). Furthermore, taxifolin completely restored decreased cerebral blood flow and cerebrovascular reactivity in Tg-SwDI mice (n = 4–6). An in vitro thioflavin-T assay showed taxifolin treatment resulted in efficient inhibition of amyloid-β1-40 assembly. In addition, a filter trap assay and ELISA showed Tg-SwDI mouse brain homogenates exhibited significantly reduced levels of amyloid-β oligomers in vivo after taxifolin treatment (n = 4–5), suggesting the effects of taxifolin on CAA are attributable to the inhibition of amyloid-β oligomer formation. In conclusion, taxifolin prevents amyloid-β oligomer assembly and fully sustains cognitive and cerebrovascular function in a CAA model mice. Taxifolin thus appears a promising therapeutic approach for CAA.

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Section: Methodsmentioning

confidence: 99%

Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy

Saitô

Yamamoto

Maki

et al. 2017

acta neuropathol commun

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“…The intermolecular proximities of β‐strands at positions 21 and 30 were less than 6 Å, supporting the presence of the intermolecular parallel β‐sheet in E22K‐Aβ42 aggregates as well as in wild‐type Aβ42 aggregates. These results also suggest that each conformer would not accumulate alternately but form a relatively large assembly from an intermolecular parallel β‐sheet in the aggregates 93 . The toxic conformer (Fig.…”

Section: Verification Of the Toxic Conformer Of Aβ42 Using Solid‐statmentioning

confidence: 81%

“…These results also suggest that each conformer would not accumulate alternately but form a relatively large assembly from an intermolecular parallel b-sheet in the aggregates. 93 The toxic conformer (Fig. 4a, right) would form a nucleus, resulting in the elongation of the physiological (non-toxic) conformer (Fig.…”

Section: S174 ͉mentioning

confidence: 99%

The turn formation at positions 22 and 23 in the 42‐mer amyloid β peptide: The emerging role in the pathogenesis of Alzheimer's disease

Murakami

Masuda

Shirasawa

et al. 2010

Geriatrics Gerontology Int

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One hallmark of Alzheimer's disease (AD) is the accumulation of amyloid b (Ab) peptides in the brain; Ab mainly consists of 42-mer and 40-mer peptides (Ab42 and Ab40). Ab42 plays a more critical role in the pathogenesis of AD because Ab42 aggregates much faster and is more toxic than Ab40. Therefore, there is an urgent need to elucidate the mechanism of aggregation and neurotoxicity of Ab42 to develop therapeutic agents. Here, we introduce the pathological role of Ab42 in AD and review our recent findings of the structural analysis of Ab42 using systematic proline replacement, electron spin resonance and solid-state nuclear magnetic resonance, and the new mechanism of neurotoxicity of Ab42 through the formation of radicals. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S169-S179.

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“…The spectrum reveals all intra-residual contacts in V24. The residues at positions 23 and 24 could form a turn or bend structure (Petkova et al 2005;Lührs et al 2005;Masuda et al 2008), though the precise structure of this region remains elusive. Furthermore, this spectrum reveals the presence of two different conformations involving V24 a and V24 b .…”

Section: Numerical Simulationsmentioning

confidence: 99%

Sensitive 13C–13C correlation spectra of amyloid fibrils at very high spinning frequencies and magnetic fields

et al. 2011

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Sensitive 2D solid-state (13)C-(13)C correlation spectra of amyloid β fibrils have been recorded at very fast spinning frequencies and very high magnetic fields. It is demonstrated that PARIS-xy recoupling using moderate rf amplitudes can provide structural information by promoting efficient magnetization transfer even under such challenging experimental conditions. Furthermore, it has been shown both experimentally and by numerical simulations that the method is not very sensitive to dipolar truncation effects and can reveal direct transfer across distances of about 3.5-4 Å.

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Verification of the Intermolecular Parallel β-Sheet in E22K-Aβ42 Aggregates by Solid-State NMR Using Rotational Resonance: Implications for the Supramolecular Arrangement of the Toxic Conformer of Aβ42

Cited by 18 publications

References 20 publications

Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy

Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy

The turn formation at positions 22 and 23 in the 42‐mer amyloid β peptide: The emerging role in the pathogenesis of Alzheimer's disease

Sensitive 13C–13C correlation spectra of amyloid fibrils at very high spinning frequencies and magnetic fields

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