biostudies-literatureYagi-Utsumi MMinistry of Education, Culture, Sports, Science and TechnologyPrecursory Research for Embryonic Science and TechnologyExploratory Research Center on Life and Living Systems, National Institutes of Natural SciencesJapan Society for the Promotion of ScienceNagoya City University2648-2657https://www.ebi.ac.uk/biostudies/studies/S-EPMC10401643biostudies-literatureUnknown14(15)Alzheimer's disease (AD) is associated with progressive accumulation of amyloid-β (Aβ) cross-β fibrils in the brain. Aβ species tightly associated with GM1 ganglioside, a glycosphingolipid abundant in neuronal membranes, promote amyloid fibril formation; therefore, they could be attractive clinical targets. However, the active conformational state of Aβ in GM1-containing lipid membranes is still unknown. The present solid-state nuclear magnetic resonance study revealed a nonfibrillar Aβ assemblage characterized by a double-layered antiparallel β-structure specifically formed on GM1 ganglioside clusters. Our data show that this unique assemblage was not transformed into fibrils on GM1-containing membranes but could promote conversion of monomeric Aβ into fibrils, suggesting that a solvent-exposed hydrophobic layer provides a catalytic surface evoking Aβ fibril formation. Our findings offer structural clues for designing drugs targeting catalytically active Aβ conformational species for the development of anti-AD therapeutics.ACS chemical neuroscienceThe Double-Layered Structure of Amyloid-β Assemblage on GM1-Containing Membranes Catalytically Promotes Fibrillization.PMC1040164322EXC338JP19K05552JP21K060402212008JPMJPR22AC23EXC305JPMXP09S19MS1049JP21K061182222004JP16K05858JPMXP09S18MS1087JPMXP09S18MS1055JPMXP09S17MS1095JP19K07041Nishimura KYagi-Utsumi MOkumura HKato KItoh SGYanagisawa KfalseThe Double-Layered Structure of Amyloid-β Assemblage on GM1-Containing Membranes Catalytically Promotes Fibrillization.Alzheimer's disease (AD) is associated with progressive accumulation of amyloid-β (Aβ) cross-β fibrils in the brain. Aβ species tightly associated with GM1 ganglioside, a glycosphingolipid abundant in neuronal membranes, promote amyloid fibril formation; therefore, they could be attractive clinical targets. However, the active conformational state of Aβ in GM1-containing lipid membranes is still unknown. The present solid-state nuclear magnetic resonance study revealed a nonfibrillar Aβ assemblage characterized by a double-layered antiparallel β-structure specifically formed on GM1 ganglioside clusters. Our data show that this unique assemblage was not transformed into fibrils on GM1-containing membranes but could promote conversion of monomeric Aβ into fibrils, suggesting that a solvent-exposed hydrophobic layer provides a catalytic surface evoking Aβ fibril formation. Our findings offer structural clues for designing drugs targeting catalytically active Aβ conformational species for the development of anti-AD therapeutics.2023-01-01T00:00:00Z2023 Aug2025-04-26T11:30:05.318Z2025-04-06T13:42:39.617ZS-EPMC104016433748265810.1021/acschemneuro.3c00192