Three structural features of functional food components and herbal medicine with amyloid β42 anti-aggregation properties
Open accessAbstract
Aggregation of amyloid β42 (Aβ42) is one of the hallmarks of Alzheimer’s disease (AD). There are numerous naturally occurring products that suppress the aggregation of Aβ42, but the underlying mechanisms remain to be elucidated. Based on NMR and MS spectroscopic analysis, we propose three structural characteristics found in natural products required for the suppressive activity against Aβ42 aggregation (i.e., oligomerization by targeting specific amino acid residues on this protein). These characteristics include (1) catechol-type flavonoids that can form Michael adducts with the side chains of Lys16 and 28 in monomeric Aβ42 through flavonoid autoxidation; (2) non-catechol-type flavonoids with planarity due to α,β-unsaturated carbonyl groups that can interact with the intermolecular β-sheet region in Aβ42 aggregates, especially aromatic rings such as those of Phe19 and 20; and (3) carboxy acid derivatives with triterpenoid or anthraquinoid that can generate a salt bridge with basic amino acid residues such as Lys16 and 28 in the Aβ42 dimer or trimer. Here, we summarize the recent body of knowledge concerning amyloidogenic inhibitors, particularly in functional food components and Kampo medicine, and discuss their application in the treatment and prevention of AD.
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A phase 2b study on elenbecestat in amyloid-PET-positive patients with mild cognitive impairment, prodromal Alzheimer disease, or mild Alzheimer disease showed decreased cerebrospinal fluid amyloid-beta levels in a dose-dependent manner but no significant improvements in Alzheimer's Disease Composite Score or CDR-SB score.
“A phase 2b study on elenbecestat in amyloid-PET-positive patients with MCI, prodromal AD, or mild AD showed decreased CSF Aβ levels in a dose-dependent manner but no significant improvements in the Alzheimer’s Disease Composite Score or CDR-SB score [50, 51].”
From Clinical trials of new drugs for Alzheimer disease (2020) · cites this paper as [51]
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Experimental — accuracy not yet measuredIn a phase 2b study of elenbecestat (E2609), a BACE-1 inhibitor, in amyloid-PET people with MCI, prodromal AD, or mild AD, dose-dependent reduction in CSF Aβ levels was noted.
“A phase 2b study of E2609 (elenbecestat), a BACE-1 inhibitor, in amyloid-PET people with MCI, prodromal AD, or mild AD was performed and reduced dose-dependent in CSF A levels was noted.”
From An update on the novel and approved drugs for Alzheimer disease (2022) · cites this paper as Murakami et al., 2019
In the phase 2b study of elenbecestat, there was no significant change in AD Composite Score or CDR-SB score.
“There is no significant change in AD. Composite Score or CDR-SB score (Murakami et al., 2019).”
From An update on the novel and approved drugs for Alzheimer disease (2022) · cites this paper as Murakami et al., 2019
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Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid β-protein fibrils
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“Caffeoylquinic acid is found in sweet potatoes, propolis, and coffee beans, and 3,4,5-tri-O-caffeoylquinic acid is a most potent analogue [51].”
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Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy
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“(+)-Taxifolin Tg-SwDI SP, oligomer decreased Improved (MWM) Impaired CBF restored [49,50]”
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BackgroundInhibition of Amyloid β Aggregation by Acteoside, a Phenylethanoid Glycoside
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“Acteoside [52] from Orobanche minor includes both caffeoyl acid and hydroxytyrosol, whereas oraposide [53] from Orobanche minor, hispidin and phelligridins [54] from Inonotus obliquus, and clovamide [55] from Trifolium pratense contain caffeoyl acid alone.”
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“Given that galangin, without the hydroxyl groups in the B-ring, is inactive, at least one hydroxyl group in the B-ring could be essential to its anti-aggregative ability [59].”
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“Ion mobility-mass spectrometry (IM-MS) is a powerful tool for measuring metastable oligomers to detect individual ions dependent on molecular size and drift time because of the inherent tendency of native oligomers to form structurally heterogeneous assemblies with the same mass-to-charge ratio (m/z) [77–79]; IM-MS ca…”
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“Moreover, quercetin and its glycoside [56] are anti-oxidant flavonoids found in Tamarix gallica.”
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“In positron emission tomography studies by Kan and coworkers, a small amount (<1%) of intravenous-injected nobiletin was detected [98].”
Background3,3′,4′,5,5′-Pentahydroxyflavone is a potent inhibitor of amyloid β fibril formation
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“Actually, we validated the potential of uncarinic acids A–D such as triterpenoid carboxy acids [76] from Uncaria rhynchophylla, also known as chotoko (a shoyaku), which are specific inhibitors of the nucleation phase.”
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“It must be noted that HFIP-treated Aβ42 forms a α-helix structure (but not a random structure) even before aggregation [36].”
BackgroundMethodInfluentialSynthetic Models of Quasi-Stable Amyloid β40 Oligomers with Significant Neurotoxicity
Irie, Y., Murakami, K., Hanaki, M., Hanaki, Y., Suzuki, T., Monobe, Y., Takai, T., Akagi, K., Kawase, T., Hirose, K., et al. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00390 · Cited by 32 · cited 1× · see citing works
“Comparing the arrival time distribution of each signal (z/n; z denotes charge, n denotes the number of oligomers), peaks corresponding to oligomeric orders can be assigned to the series of multivalent ions at least up to 24-mer [83].”
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“Maslinic acid, a similar triterpenoic acid, has been shown to protect against apoptosis induced by A42 [84].”
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“Acteoside [52] from Orobanche minor includes both caffeoyl acid and hydroxytyrosol, whereas oraposide [53] from Orobanche minor, hispidin and phelligridins [54] from Inonotus obliquus, and clovamide [55] from Trifolium pratense contain caffeoyl acid alone.”
BackgroundApomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer’s Disease
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BackgroundMechanistic analyses of the suppression of amyloid β42 aggregation by apomorphine
Hanaki, M., Murakami, K., Katayama, S., Akagi, K., & Irie, K. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.01.028 · Cited by 21 · cited 1× · see citing works
“Although (R)-apomorphine is known as a dopaminergic agonist in the treatment of Parkinson’s disease due to its potent anti-oxidant activity [70], we focused on the conjugated structure of (R)-apomorphine by autoxidation [71].”
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“NMR studies showed that the first oxidized structure (APOox1) of (R)-apomorphine can target Lys16 to form a Michael adduct in the nucleation phase.”
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Inhibitory Activity of Hispidin Derivatives Isolated from Inonotus obliquus on Amyloid β Aggregation
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A Note on Design and Analysis of Clinical Trials
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Drug Discovery from Medicinal Plants against Alzheimer's Disease
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- Authors
- Murakami, K., & Irie, K.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Murakami, Kazuma
- Irie, Kazuhiro
- Venue
- Molecules
- Publisher
- MDPI AG
- Published
- 2019-06-05
- Volume
- 24
- Issue
- 11
- Pages
- 2125
- ISSN
- 1420-3049 (ISSN-L)
- PMC
- PMC6600243
- OpenAlex
- W2948703364
- Cited by
- 31
- References
- 102
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 2 · 2020: 8 · 2019: 2
- FWCI
- 0.56
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Molecules (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
- Funders
- Japan Society for the Promotion of Science (grant number 26221202 to K.I. and K.M., 16H06194 to K.M.)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta 42, protein aggregation inhibition, Alzheimer's disease, Michael adducts, triterpenoids, salt bridges, Kampo medicine, functional food ingredients
- MeSH terms
- Animals, Flavonoids, Humans, Amyloid beta-Peptides, Herbal Medicine, Functional Food, Polymerization, Protein Aggregates
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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