Association between cerebral organoid electrophysiological alterations and amyloid-β 42/40 ratio

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F25%3A00142648" target="_blank" >RIV/00216224:14110/25:00142648 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14110/25:00142649

Výsledek na webu

<a href="https://www.ecnp.eu/congress2025/programme/provisional-programme/#!abstractdetails/0000695410" target="_blank" >https://www.ecnp.eu/congress2025/programme/provisional-programme/#!abstractdetails/0000695410</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Association between cerebral organoid electrophysiological alterations and amyloid-β 42/40 ratio

Popis výsledku v původním jazyce

Introduction: Amyloid-β (Aβ) oligomers are implied to enhance excitability and cause irreversible neural alterations. Such activity appears in preclinical stages of AD, particularly in the hippocampus, which also contributes to epileptogenic loci in temporal epilepsy. By investigating electrical changes in Alzheimer's-like cerebral organoid models, we are recreating the microenvironment corresponding to the substrate from which epileptogenic activity emerges. Main aim: To examine the effect of neurodegenerative marker accumulation on neuronal excitability in Alzheimer's models. Methods: Electrical activity was measured in vitro at 37°C by the multielectrode array technique in cerebral organoids, derived from hiPSCs of a patient with a familial form of AD (n = 15) and an unrelated healthy control (n = 16), during differentiation days (DD) DD57-DD140. The analysis was performed on bursts detected between 5. - 15. minute of the recording. To investigate the neuronal connectivity, the global synchrony index was estimated from detected spikes. Aβ concentrations were measured at DD60, DD90, and DD120 using ELISA, with Aβ42/40 ratio used for the analysis. Three measurement runs were arranged by differentiation day (DD) for Aβ42/40 levels and activity correlation. Normal distribution was rejected using the Shapiro-Wilk test. The significance of differences among samples was verified using the Mann-Whitney or Wilcoxon tests. The correlation between parameters was evaluated using Spearman's rank-order method. Results: An elevation in electrical activity was observed in AD, especially in metrics such as the percentage of active electrodes (WT 1.7 vs. AD 18.7 %, P &lt; 0.001), global synchrony index (WT 0.34 vs. AD 0.39, P &lt; 0.001), intraburst spike number (WT 6.75 vs. AD 10.63, P &lt; 0.001), intraburst spike frequency (WT 37.2 vs. AD 41.7 Hz, P &lt; 0.001), and burst duration (WT 0.20 vs. AD 0.24 s, P &lt; 0.05). In two out of three recorded runs, the Aβ42/40 was elevated in AD, specifically at DD120 (WT 0.029 vs. AD 0.070, P &lt; 0.05). Furthermore, a significant increase in Aβ42/40 of AD was observed between DD60 and DD90 (DD60: 0.062 vs. DD90: 0.070, P &lt; 0.01). A strong correlation between Aβ42/40 ratio and activity parameters was found in AD, whereas the correlation with activity parameters in WT was not significant, e.g. Aβ42/40 vs. intraburst spike number (AD: rs = 0.7782, P &lt; 0.05), or Aβ42/40 vs. intraburst spike frequency (AD: rs = 0.7333, P &lt; 0.05). Conclusion: The findings indicate that AD organoids exhibit an increase in spontaneous electrical activity compared to controls, alongside a significant increase in Aβ42/40 ratio correlating with this activity. This suggests a potential association between the Aβ42/40 ratio and neuronal excitability, warranting further exploration of these relationships.

Název v anglickém jazyce

Association between cerebral organoid electrophysiological alterations and amyloid-β 42/40 ratio

Popis výsledku anglicky

Introduction: Amyloid-β (Aβ) oligomers are implied to enhance excitability and cause irreversible neural alterations. Such activity appears in preclinical stages of AD, particularly in the hippocampus, which also contributes to epileptogenic loci in temporal epilepsy. By investigating electrical changes in Alzheimer's-like cerebral organoid models, we are recreating the microenvironment corresponding to the substrate from which epileptogenic activity emerges. Main aim: To examine the effect of neurodegenerative marker accumulation on neuronal excitability in Alzheimer's models. Methods: Electrical activity was measured in vitro at 37°C by the multielectrode array technique in cerebral organoids, derived from hiPSCs of a patient with a familial form of AD (n = 15) and an unrelated healthy control (n = 16), during differentiation days (DD) DD57-DD140. The analysis was performed on bursts detected between 5. - 15. minute of the recording. To investigate the neuronal connectivity, the global synchrony index was estimated from detected spikes. Aβ concentrations were measured at DD60, DD90, and DD120 using ELISA, with Aβ42/40 ratio used for the analysis. Three measurement runs were arranged by differentiation day (DD) for Aβ42/40 levels and activity correlation. Normal distribution was rejected using the Shapiro-Wilk test. The significance of differences among samples was verified using the Mann-Whitney or Wilcoxon tests. The correlation between parameters was evaluated using Spearman's rank-order method. Results: An elevation in electrical activity was observed in AD, especially in metrics such as the percentage of active electrodes (WT 1.7 vs. AD 18.7 %, P &lt; 0.001), global synchrony index (WT 0.34 vs. AD 0.39, P &lt; 0.001), intraburst spike number (WT 6.75 vs. AD 10.63, P &lt; 0.001), intraburst spike frequency (WT 37.2 vs. AD 41.7 Hz, P &lt; 0.001), and burst duration (WT 0.20 vs. AD 0.24 s, P &lt; 0.05). In two out of three recorded runs, the Aβ42/40 was elevated in AD, specifically at DD120 (WT 0.029 vs. AD 0.070, P &lt; 0.05). Furthermore, a significant increase in Aβ42/40 of AD was observed between DD60 and DD90 (DD60: 0.062 vs. DD90: 0.070, P &lt; 0.01). A strong correlation between Aβ42/40 ratio and activity parameters was found in AD, whereas the correlation with activity parameters in WT was not significant, e.g. Aβ42/40 vs. intraburst spike number (AD: rs = 0.7782, P &lt; 0.05), or Aβ42/40 vs. intraburst spike frequency (AD: rs = 0.7333, P &lt; 0.05). Conclusion: The findings indicate that AD organoids exhibit an increase in spontaneous electrical activity compared to controls, alongside a significant increase in Aβ42/40 ratio correlating with this activity. This suggests a potential association between the Aβ42/40 ratio and neuronal excitability, warranting further exploration of these relationships.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů