ACROBiosystems offers comprehensive Organoid Toolbox solutions with advanced technology and expert services, including ready-to-use iPSC-derived organoids, cryopreserved organoids, organoid differentiation kits, and customized organoid services. These solutions support breakthroughs in disease modeling, drug screening, efficacy, and safety evaluation, driving innovation in biomedical research.

From Traditional Models to Brain Organoids: Unveiling New Perspectives on Neurological Diseases

Neurological diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) have long posed challenges in medical research due to their complex pathogenesis and lack of effective treatments. Traditional research methods, such as animal models and 2D cell cultures, often fail to capture disease complexity. The advent of induced pluripotent stem cells (iPSCs) and 3D brain organoid technology provides highly biomimetic human brain tissue models. Brain organoids can simulate brain development, neural network formation, and complex cell interactions, making them valuable for disease modeling, gene therapy tool screening, and drug evaluation, supporting precision medicine.

Figure 1. Protocol Diagram of Brain Organoid Differentiation.

Applications of Brain Organoids in Neurological Disease Modeling

AD and PD are neurodegenerative diseases caused by abnormal protein aggregation. iPSC-derived brain organoids effectively reproduce the pathological mechanisms of these diseases in vitro, simulating the abnormal aggregation of Tau protein or α-synuclein (α-syn). This enables researchers to explore pathological changes of diseases and offers experimental insights to support the development of potential therapeutic strategies.

AD Modeling: Visualization of Tau Protein Aggregation
Brain organoids (Cat. No. CIPO-BWL001K) differentiated using the Organoid Differentiation Kit (Cat. No. RIPO-BWM001K) were co-cultured with varying concentrations of Tau Pre-formed Fibrils (PFFs) (Cat. No. TAU-H5113) to establish an AD model (Figure 2). The addition of Tau PFFs significantly induced Tau aggregation, with increasing concentrations of PFFs leading to enhanced Tau aggregation, characterized by upregulation of p-Tau181 expression (Cat. No. PT1-Y2073).

Figure 2. Tau PFFs induce Tau aggregation in brain organoids.

PD Modeling: Degeneration of Dopamine Neurons
Brain organoids (Cat. No. CIPO-BWL001K) differentiated using the Organoid Differentiation Kit (Cat. No. RIPO-BWM001K) were co-cultured with varying concentrations of α-syn PFFs (Cat. No. ALN-H5115) to establish a PD model (Figure 3). After the addition of α-syn PFFs, the expression of MAP2 and TH was disrupted, indicating damage to mature neurons (MAP2) and dopamine neurons (TH) caused by α-syn PFFs.

Figure 3. α-syn PFFs induce neuronal damage in brain organoids.

Application of Brain Organoids in the Optimization of Gene Therapy Vectors

Adeno-associated virus (AAV) vectors are widely used in gene therapy, and the selection of serotypes is crucial for the success of gene delivery. Brain organoids serve as a screening platform that closely mimics the complex environment of the human brain, enabling precise evaluation of the transduction efficiency of various AAV serotypes. This approach facilitates the identification of the most effective serotype, improving the targeted delivery and gene expression efficiency of AAV vectors in neural tissues.

Using brain organoids cultured for 101 days (Cat. No. CIPO-BWL002K), different AAV serotypes were applied for transduction. Fluorescence microscopy observations (Figure 4) revealed that the IVB-2 serotype demonstrated higher GFP expression levels in transduced brain organoids compared to other serotypes, indicating its superior transduction efficiency and greater potential as a gene therapy vector.

Figure 4. GFP fluorescence expression in brain organoids transduced with different AAV serotypes.

Application of Brain Organoids in Neurological Drug Evaluation

Gamma-aminobutyric acid (GABA) is a key inhibitory neurotransmitter that reduces neuronal activity by acting on GABA receptors, maintaining the balance of neural excitability. Dysfunctions in the GABA receptor-mediated signaling system can lead to excessive neuronal excitability, potentially resulting in various neurological disorders or dysfunctions.

Effects of Muscimol on Neural Activity in Brain Organoids
Muscimol, a GABA-A (GABAA) receptor agonist, enhances the inhibitory effect of GABA on neuronal activity by activating GABAA receptors. The impact of Muscimol on neuronal activity was evaluated using brain organoids (Cat. No. CIPO-BWL001K) (Figure 5). Control brain organoids exhibited intense network burst activity and high mean spike firing rate, indicating high neuronal activity. In contrast, brain organoids treated with Muscimol showed significantly reduced network burst activity and a marked decrease in spike firing rate, demonstrating that Muscimol effectively suppresses neuronal excitability through GABA receptor activation.

Figure 5. Effects of Muscimol treatment on neural activity in brain organoids.

Effects of Picrotoxin on Neural Activity in Brain Organoids
Picrotoxin, a GABAA receptor antagonist, blocks the inhibitory signals mediated by GABAA receptors, thereby relieving the inhibition on neuronal activity. In brain organoids (Cat. No. CIPO-BWL001K) treated with Picrotoxin (Figure 6), synchronized network burst activity was observed, indicating that synaptic connections between neurons had been established. This synchronized bursting is commonly considered a hallmark of mature synaptic connectivity in neuronal networks. Therefore, Picrotoxin promotes neuronal activity and network maturation by blocking the inhibitory effect of GABAA receptors.

Figure 6. Effects of Picrotoxin treatment on neural activity in brain organoids.

Conclusion

Brain organoids, as highly biomimetic 3D neural models, are becoming a key platform for neurological disease research and drug development. By simulating complex neural environments, brain organoids not only replicate pathological changes in diseases like AD and PD, but also provide precise tools for gene therapy and drug evaluation. ACROBiosystems will continue to advance organoid technology, driving progress in neurological disease research and drug development.

Reference

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