Alzheimer's disease (AD) is neuropathologically defined by extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Recent studies have identified AD in people who received cadaveric pituitary-derived growth hormone (GH) contaminated with Aβ seeds, offering a rare chance to examine potential Aβ seeding in humans. Nevertheless, the structural properties of Aβ and tau aggregates in these patients have remained uncharacterized. Using cryo-electron microscopy (cryo-EM), we characterized the structures of Aβ and tau filaments from the frontal cortex of an AD patient who received Aβ-contaminated GH replacement therapy. We identified and reconstructed type I and type II Aβ42 filaments with resolutions reaching 3.1 Å and 3.2 Å, respectively, exhibiting structural similarity to those found in sporadic AD. In addition, tau filaments showed the classical polymorphs of paired helical filaments (PHFs) and straight filaments (SFs) as previously reported in AD. Our findings indicate that the folds of Aβ and tau filaments are highly conserved across different disease contexts. This work represents the first structural analysis of amyloid aggregates in treatment-associated AD and will provide new insights into Aβ aggregation mechanisms underlying AD pathogenesis.
Alhadidy et al. (Sun,) studied this question.