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-Structure paper
タイトル | Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer's disease brains. |
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ジャーナル・号・ページ | Neuron, Vol. 111, Issue 13, Page 2012-22020.e4, Year 2023 |
掲載日 | 2023年7月5日 |
著者 | Andrew M Stern / Yang Yang / Shanxue Jin / Keitaro Yamashita / Angela L Meunier / Wen Liu / Yuqi Cai / Maria Ericsson / Lei Liu / Michel Goedert / Sjors H W Scheres / Dennis J Selkoe / |
PubMed 要旨 | Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed ...Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed to be upstream initiators of synaptic dysfunction, but little is known about their structures. We now report the unexpected presence of Aβ fibrils in synaptotoxic high-speed supernatants from AD brains extracted by soaking in an aqueous buffer. The fibrils did not appear to form during preparation, and their counts by EM correlated with Aβ ELISA quantification. Cryo-EM structures of aqueous Aβ fibrils were identical to those from sarkosyl-insoluble homogenates. The fibrils in aqueous extracts were labeled by lecanemab, an Aβ aggregate-directed antibody reported to improve AD cognitive outcomes. Lecanemab provided protection against aqueous fibril synaptotoxicity. We conclude that fibrils are abundant in aqueous extracts from AD brains and have the same structures as those from plaques. These findings have implications for AD pathogenesis and drug design. |
リンク | Neuron / PubMed:37167969 / PubMed Central |
手法 | EM (らせん対称) |
解像度 | 2.9 - 3.7 Å |
構造データ | EMDB-15770, PDB-8azs: EMDB-15771, PDB-8azt: EMDB-15772, PDB-8azu: |
由来 |
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キーワード | PROTEIN FIBRIL / amyloid / filaments / Abeta42 / amyloid-beta / cryo-EM / tau / PHF |