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Patient-Derived PSEN1 Cerebral Organoids Revealed Parallel Development of Amyloid-β Accumulation and Network
Andrijana Angelovski1,2, Hana Hribkova3, Jiri Sedmik3
1Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.
Cellular and Molecular Neurobiology
|July 20, 2026
Summary
Alzheimer's disease organoids show early network hyperexcitability linked to amyloid-beta (Aβ) changes. This suggests Aβ may drive early brain dysfunction in preclinical Alzheimer's disease (AD).
Area of Science:
- Neuroscience
- Stem Cell Biology
- Genetics
Background:
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing dementia and brain atrophy.
- Familial AD mutations, like PSEN1 A246E, offer insights into early disease mechanisms.
- Cerebral organoids from patient-derived cells model human brain development and disease.
Purpose of the Study:
- To investigate the temporal relationship between amyloid-beta (Aβ) dysregulation and neuronal activity in early Alzheimer's disease.
- To utilize patient-derived cerebral organoids carrying the PSEN1 A246E variant as a model system.
- To explore potential Aβ-induced changes in neuronal excitability during preclinical AD stages.
Main Methods:
- Generation of cerebral organoids from human induced pluripotent stem cells (hiPSCs) with the familial PSEN1 A246E variant.
- Multielectrode array (MEA) recordings to monitor spontaneous neuronal activity from differentiation day 60 (DD60) to DD130.
- Analysis of amyloid-beta (Aβ) levels (Aβ42/40 ratio) and aggregate size in relation to network activity metrics.
Main Results:
- Alzheimer's disease (AD) organoids exhibited transient network hyperexcitability and hypersynchrony compared to wild-type (WT) controls.
- A gradual decline in neuronal activity was observed in AD organoids after the hyperexcitability phase.
- Elevated Aβ42/40 ratio and larger Aβ aggregate size correlated positively with network activity during the hyperexcitability stage.
Conclusions:
- Amyloid-beta (Aβ) dysregulation may contribute to transient network hyperexcitability in the early stages of Alzheimer's disease.
- Patient-derived cerebral organoids serve as a valuable translational model for studying early network dysfunction in AD.
- Findings inform future research on Aβ's role in preclinical AD excitability changes.
