| Popis |
Introduction: Accumulation of amyloid-ß (Aß) and hyperphosphorylated tau (p-tau) is a characteristic feature of Alzheimer's disease (AD), leading to cognitive decline. Hyperexcitability is often associated with prodromal AD stages. Several possible causes of AD hyperexcitability, including the accumulation of neurodegenerative markers, are considered, but the relationship has not been directly proved. Hence, we aimed to investigate this relationship in cerebral organoids of a patient suffering from familial AD and carrying a PSEN1 variant and an unrelated healthy control (WT). Methods: Spontaneous electrical activity of WT (n = 16/3) and AD (n = 15/3) cerebral organoids was recorded twice per week between the differentiation day (DD) 60 and 139 at 37?°C using the multielectrode array technique (MEA2100-Lite-System, 60MEA-200/30iR-Ti; sampling rate 25 kHz). After filtering (300–3000 Hz), following parameters were evaluated: (i.) spikes – spike frequency (above 0.1?Hz), spike amplitude (above -6.5SD of the noise), interspike interval coefficient of variation (ISIcv), number of active electrodes, global synchrony index (GSI); (ii.) bursts – intraburst spike number (above 5) and frequency, burst duration (above 100 ms), interburst interval (above 100 ms), burst frequency, number of active electrodes. Values at the 3-week peak of the activity were compared. Regarding NAPs, the content of p-tau and Aß aggregate size (immunocytochemistry), and secreted Aß42/Aß40 (ELISA) were examined. Results: We observed significantly higher connectivity in AD cerebral organoids compared to WT ones: number of active electrodes in spike activity (AD 22.0 vs. WT 5.9, P < 0.001) and burst activity (AD 18.7 vs. WT 1.7, P < 0.001), spike amplitude (AD 25.2 vs. WT 24.1 ?V, P < 0.05), GSI (AD 0.40 vs. WT 0.34, P < 0.001), intraburst spike number (AD 10.6 vs. WT 6.8, P < 0.001) and frequency (AD 41.7 vs. WT 37.2 Hz, P < 0.001), and burst duration (AD 242 vs. WT 208.3 ms, P < 0.05). A positive correlation was observed between the secreted Aß42/Aß40 and the number of active electrodes as well as GSI in the spike activity (the Spearman´s correlation coefficient rs = 0.94, P < 0.05, and rs = 1.00, P < 0.01, respectively), and between Aß aggregate size and GSI (rs = 0.94, P < 0.05). Conclusion: We demonstrated that Aß42/Aß40 and Aß deposits positively correlated with neuronal connectivity during spontaneous electrical activity in early AD. In contrast, the detected p-tau deposits were limited, thus, their role in the development of altered neuronal excitability in early AD is unlikely.
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