Polyphenolic glycosides and aglycones utilize opposing pathways to selectively remodel and inactivate toxic oligomers of amyloid β.
Polyphenolic glycosides and aglycones utilize opposing pathways to selectively remodel and inactivate toxic oligomers of amyloid β.
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DOI：
10.1002/cbic.201100123
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发表时间：
2011-07-25
期刊：
影响因子：
3.2
通讯作者：
Tessier, Peter M.
中科院分区：
文献类型：
--
作者：
Ladiwala, Ali Reza A.;Mora-Pale, Mauricio;Lin, Jason C.;Bale, Shyam Sundhar;Fishman, Zachary S.;Dordick, Jonathan S.;Tessier, Peter M.
大量证据表明，与阿尔茨海默病相关的Aβ42肽的可溶性前原纤维寡聚体是最具细胞毒性的聚集Aβ同种型。有限的先前工作已经揭示，能够将Aβ寡聚体重塑为无毒构象异构体的芳香族化合物通常通过将其转化为非途径聚集体而不是将其解离为单体来实现。为了鉴定能够在亚化学计量浓度下选择性地将毒性Aβ寡聚体解离成可溶性肽的小分子拮抗剂，我们研究了多酚糖苷配基及其糖苷用于重塑Aβ可溶性寡聚体的途径。我们发现，11种不同大小和结构的多酚苷元利用相同的重塑途径，从而Aβ寡聚体迅速转化为大的、非途径聚集体。引人注目的是，我们发现这些多酚的糖苷都利用了一种独特的重塑途径，其中Aβ寡聚体迅速解离成可溶性的解聚肽。这种解聚活性是糖苷配基和糖基部分的协同组合，因为多酚和糖的组合不能解聚Aβ寡聚体。我们还发现多酚糖苷和苷元使用相同的相反途径来重塑Aβ纤维。重要的是，这两类多酚不能重塑无毒Aβ低聚物（其在大小和形态上与Aβ可溶性低聚物不可区分）或促进新鲜解聚的Aβ肽的聚集，这表明它们对重塑有毒Aβ构象异构体具有特异性。我们期望这些和相关的小分子将成为研究Aβ介导的毒性的构象和细胞基础的强大化学探针。
Substantial evidence suggests that soluble prefibrillar oligomers of the Aβ42 peptide associated with Alzheimer’s disease are the most cytotoxic aggregated Aβ isoform. Limited previous work has revealed that aromatic compounds capable of remodeling Aβ oligomers into non-toxic conformers typically do so by converting them into off-pathway aggregates instead of dissociating them into monomers. Towards identifying small molecule antagonists capable of selectively dissociating toxic Aβ oligomers into soluble peptide at substoichiometric concentrations, we have investigated the pathways used by polyphenol aglycones and their glycosides to remodel Aβ soluble oligomers. We find that eleven polyphenol aglycones of variable size and structure utilize the same remodeling pathway whereby Aβ oligomers are rapidly converted into large, off-pathway aggregates. Strikingly, we find that glycosides of these polyphenols all utilize a distinct remodeling pathway in which Aβ oligomers are rapidly dissociated into soluble, disaggregated peptide. This disaggregation activity is a synergistic combination of the aglycone and glycone moieties since combinations of polyphenols and sugars fail to disaggregate Aβ oligomers. We also find that polyphenolic glycosides and aglycones use the same opposing pathways to remodel Aβ fibrils. Importantly, both classes of polyphenols fail to remodel non-toxic Aβ oligomers (which are indistinguishable in size and morphology to Aβ soluble oligomers) or promote aggregation of freshly disaggregated Aβ peptide, revealing that they are specific for remodeling toxic Aβ conformers. We expect that these and related small molecules will be powerful chemical probes for investigating the conformational and cellular underpinnings of Aβ-mediated toxicity.
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影响因子：
64.8
作者：
Chien, P;Weissman, JS
通讯作者：
Weissman, JS
影响因子：
15.1
作者：
Kayed R;Head E;Sarsoza F;Saing T;Cotman CW;Necula M;Margol L;Wu J;Breydo L;Thompson JL;Rasool S;Gurlo T;Butler P;Glabe CG
通讯作者：
Glabe CG
影响因子：
4.7
作者：
Hong HS;Rana S;Barrigan L;Shi A;Zhang Y;Zhou F;Jin LW;Hua DH
通讯作者：
Hua DH
影响因子：
25
作者：
Cleary, JP;Walsh, DM;Ashe, KH
通讯作者：
Ashe, KH
影响因子：
4.7
作者：
Lambert, MP;Viola, KL;Klein, WL
通讯作者：
Klein, WL