While the tissue engineering approaches mentioned above do produce AD-like phenotypes and are highly amenable to experimental manipulation, the process is labor-intensive and requires the exogenous overexpression of disease-relevant mutations or factors. In the current work, we have adapted a scaffold-free culture approach to generate neural organoids from AD patient derived cells. These 3D cultures efficiently produce robust AD phenotypes, without genetic manipulation or exogenous toxins. Although neural organoids have been shown to be extremely useful for the study of neurodevelopmental phenomena and prenatal injury [51–53,60–63], no previous study had applied this system to the study of age-related neurodegeneration. We show that, by “aging” these cultures in vitro, we can observe the spontaneous emergence of hallmark AD pathologies such as amyloid aggregates and hyperphosphorylated tau. Importantly, we demonstrate that this model system is amenable to experimental manipulation, such as drug treatment, and that these phenotypes are robust enough to be recapitulated across multiple cells lines derived from different AD patients.
