Hoq, Md RejaulFernandez, AnllelyVago, Frank S.Hallinan, Grace I.Bharath, Sakshibeedu R.Li, DaoyiOzcan, Kadir A.Garringer, Holly J.Jiang, WenVidal, RubenGhetti, Bernardino2024-10-092024-10-092024-08-15Hoq MR, Fernandez A, Vago FS, et al. Cryo-EM structures of cotton wool plaques' amyloid β and of tau filaments in dominantly inherited Alzheimer disease. Acta Neuropathol. 2024;148(1):20. Published 2024 Aug 15. doi:10.1007/s00401-024-02786-yhttps://hdl.handle.net/1805/43849Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-β (Aβ) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aβ peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aβ and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aβ filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aβ filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aβ filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalPSEN1AβCryo-EMDIADNeurodegenerationTauArticle