Angelovski, A.; Hribkova, H.; Sedmik, J.; Liscakova, B.; Svecova, O.; Cesnarikova, S.; Amruz Cerna, K.; Pospisilova, V.; Kral, M.; Kolajova, M.; Klimes, P.; Bohaciakova, D.; Marketa, B.

Alzheimers disease (AD) is a neurodegenerative disorder characterised by progressive dementia, brain atrophy, and ultimately death. Using cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) carrying the familial PSEN1 A246E variant, we investigated the temporal relationship between amyloid-beta (Abeta) dysregulation and spontaneous neuronal activity. Multielectrode array recordings from the differentiation day 60 (DD60) to at least DD130 revealed that AD organoids exhibited transient hyperexcitability and hypersynchrony compared with wild-type (WT) controls, followed by a gradual decline in activity. During the enhanced excitability stage, both elevated Abeta42/40 and Abeta aggregate size showed positive correlations with the percentage of active electrodes and the global synchrony index (GSI) in AD organoids. These findings indicate that Abeta dysregulation might contribute to transient network hyperexcitability in early AD. The results also suggest that patient-derived cerebral organoids may serve as a translational model to examine early network dysfunction and inform future investigations of potential Abeta-induced changes in excitability during the preclinical stages of AD.