Fibriler proteinlere maruz kalma, kortikal organoidlerde yaygın sızmaya ancak sadece hafif tau patolojisine yol açar.

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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.

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