Cryo-EM structures of amyloid-β and tau filaments in Down syndrome

• Published in: Nature structural & molecular biology Vol. 31; no. 6; pp. 903 - 909
• Main Authors: Fernandez, Anllely, Hoq, Md Rejaul, Hallinan, Grace I., Li, Daoyi, Bharath, Sakshibeedu R., Vago, Frank S., Zhang, Xiaoqi, Ozcan, Kadir A., Newell, Kathy L., Garringer, Holly J., Jiang, Wen, Ghetti, Bernardino, Vidal, Ruben
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2024; Nature Publishing Group
• Subjects: 631/535/1258/1259; 692/699; Adult; Adults; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Brain - metabolism; Brain - pathology; Clinical trials; Cryoelectron Microscopy; Down syndrome; Down Syndrome - metabolism; Down Syndrome - pathology; Down's syndrome; Filaments; Humans; Life Sciences; Membrane Biology; Models, Molecular; Neurodegenerative diseases; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Protein Structure; Tau protein; tau Proteins - chemistry; tau Proteins - metabolism; tau Proteins - ultrastructure; β-Amyloid
• ISSN: 1545-9993; 1545-9985; 1545-9985
• DOI: 10.1038/s41594-024-01252-3

Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ 40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ 42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials. Here, using cryo-EM, authors reveal that amyloid-β and tau are identical in Alzheimer disease and Down syndrome. This has implications for assessing whether adults with Down syndrome could be included in Alzheimer disease clinical trials.