Brain organoids are self-assembled three-dimensional aggregates generated from pluripotent stem cells. They offer a reproducible, optimized platform filling in the gap that traditional models for neurodegenerative diseases struggle to address.
In a recent study from The Scripps Research Institute, Sergio R. Labra and colleagues developed an advanced human cerebrocortical organoid (CO) model to investigate early events in familial Alzheimer’s disease (AD). Using human iPSCs, the team generated organoids carrying heterozygous mutations in key AD-associated genes, PSEN1 (PSEN1ΔE9/WT, PSEN1M146V/WT) or APP (APPSwe/WT), and compared them to isogenic wild-type controls (WT/WT).
The COs were extensively characterized using immunohistochemistry, single-cell RNA sequencing, electrophysiology, and biochemical assays, demonstrating the presence of diverse neuronal and glial populations alongside disease-relevant phenotypes. Notably, using Amytracker 480, the authors confirmed the presence of Aβ aggregates in 9-month-old COs, with higher levels observed in PSEN1M146V/WT and APPSwe/WT models compared to controls (see Image). The system also responded to pharmacological intervention, with autophagy-activating compounds reducing both Aβ and Tau pathology while improving neuronal function and viability.
Taken together, these results establish this AD CO model as a robust platform for studying early mechanisms of familial AD and for evaluating candidate therapeutics. Additionally, this study represents the first reported use of Amytracker in organoids, highlighting its utility as a sensitive tool for visualizing amyloid formation in complex human disease models.
Image: Cerebricortical organoids carrying AD-associated mutations in PSEN1 (PSEN1M146V/WT) and APP (APPSwe/WT), compared to wild-type control (WT/WT), at the 9-month time point. Organoids are stained with Amytracker 480 (AmyTr), and antibodies against total Aβ and Aβ1-42. Scale bar, 100 µm. Adapted from Figure S6D, Labra et al. 2026 (CC BY 4.0).