Alzheimer’s Disease Brain Organoids as a Source of Disease-Relevant Amyloid-Beta Oligomers

Amyloid plaques are a hallmark of Alzheimer's disease (AD) progression; however, the early stages of plaque formation and the specific amyloid-beta (Aβ) species involved remain difficult to study. While post-mortem tissue provides insight into end-stage mature plaques, therapeutic development requires targeting the earliest Aβ oligomers to arrest plaque formation. Furthermore, inherently toxic soluble Aβ oligomers off-pathway from plaque formation are implicated as a driving force of AD pathology. It also remains unclear if the specific nature of key disease-relevant species can be accurately replicated in preparations of synthetic peptides.. To bridge this gap, we utilize brain organoids carrying AD mutations as a biologically authentic source for Aβ peptides and oligomers. We demonstrate that these mutations do not disrupt organoid development and that the resulting conditioned media contains Aβ oligomers with disease-relevant structures. Finally, we show that these oligomers can be concentrated and segregated via differential ultracentrifugation for further experimental applications.