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TitleAbundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer's disease brains.
Journal, issue, pagesNeuron, Vol. 111, Issue 13, Page 2012-22020.e4, Year 2023
Publish dateJul 5, 2023
AuthorsAndrew 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 AbstractSoluble 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.
External linksNeuron / PubMed:37167969 / PubMed Central
MethodsEM (helical sym.)
Resolution2.9 - 3.7 Å
Structure data

EMDB-15770, PDB-8azs:
Type I amyloid-beta 42 filaments from high-spin supernatants of aqueous extracts from Alzheimer's disease brains | ABeta42
Method: EM (helical sym.) / Resolution: 2.9 Å

EMDB-15771, PDB-8azt:
Type II amyloid-beta 42 filaments from high-spin supernatants of aqueous extracts from Alzheimer's disease brains | ABeta42
Method: EM (helical sym.) / Resolution: 3.7 Å

EMDB-15772, PDB-8azu:
Paired helical tau filaments from high-spin supernatants of aqueous extracts from Alzheimer's disease brains | PHF Tau
Method: EM (helical sym.) / Resolution: 3.1 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / amyloid / filaments / Abeta42 / amyloid-beta / cryo-EM / tau / PHF

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