Exposure to fibrillar proteins leads to widespread infiltration but only mild tau pathology in cortical organoids

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders, both characterized by accumulation of aggregated proteins. In AD, the pathological deposits consist predominantly of amyloid-beta (Aβ) and tau, while alpha-synuclein (αSYN) forms inclusions in PD. However, cross-seeding often generates mixed pathologies. Emerging evidence suggests a role of astrocytes in disease spreading, but the underlying mechanisms remain unclear, partly due to limitations of mouse models in replicating early human disease. To address this, we developed a human cerebral organoid platform to study early sporadic AD/PD events. We introduced fibrillar aggregates of αSYN, Aβ, and tau directly into organoids or via astrocytes pre-exposed to the aggregates. All proteins successfully penetrated the organoids with distinct morphology and distribution patterns. Twelve weeks post-exposure, organoids exposed to Aβ or αSYN-containing astrocytes showed the highest insoluble tau levels, but none developed robust tau pathology, highlighting limitations in organoid modeling of tau pathology.