Overview: Lewy body dementia (LBD) is a difficult-to-diagnose neurodegenerative disease with symptoms similar to both Parkinson’s disease and Alzheimer’s disease, including hallucinations, cognitive impairment, and movement disorders. To study the progression of LBD, researchers developed a mini-brain model from stem cells from LBD patients that reproduced key disease features found in the human brain.
These models helped identify four promising drugs that could inhibit the accumulation of α-synuclein, a key protein associated with LBD. The mini-brains are expected to advance personalized treatment trials and potentially improve our understanding of disease mechanisms. Future studies may include adding additional cell types to obtain a more accurate model. This research could lead to meaningful advances in the treatment of LBD.
Important facts:
Mini-brain models using patient-derived stem cells can help mimic the development of LBD. The four potential drugs identified may prevent the accumulation of harmful alpha-synuclein. The model provides a platform to test targeted therapies and explore disease pathways.
Source: Mayo Clinic
Lewy body dementia (LBD) is a progressive neurodegenerative disease that shares features with both Parkinson’s disease and Alzheimer’s disease, but can be more difficult to diagnose. Symptoms include hallucinations, movement disorders, cognitive impairment, sleep disturbances, and depression.
To better understand how the disease develops, Mayo Clinic scientists created a mini-brain model in a dish that closely matches key features found in the brains of people with Lewy body dementia. Created on.
Mini brains, also known as brain organoids, are clusters of lab-grown cells that mimic the structure of the human brain. The research team also identified four drug compounds that may offer promising approaches to treating the disease.
Their findings are published in Science Advances.
Scientists say there is no cure for LBD and there are few accurate preclinical models available for research. The disease is characterized by a protein called alpha-synuclein, which is encoded by the SNCA gene. This protein is present in nerve cells in the brain and can accumulate to form clumps called Lewy bodies, which can contribute to the symptoms of dementia.
To better understand the pathology of this disease, a Mayo Clinic research team led by neuroscientist and senior author Na Zhao, MD, used preclinical Developed a brain model. , which may have caused their condition.
After the patient was diagnosed, he donated his skin cells while he was still alive. Scientists then converted the skin cells into stem cells and used them in research.
Researchers used advanced genomic techniques such as single-cell RNA sequencing, which examines the genetic material within individual cells, to create a mini-brain model that replicates the human brains of LBD patients whose brains were donated to the Mayo Clinic Brain Bank. It was shown that this reflects the changes seen in , the model becomes a valuable tool for studying how the disease progresses.
Researchers used a new model system to screen nearly 1,300 Food and Drug Administration-approved drugs and identified four candidates that may help prevent alpha-synuclein accumulation in neurons. .
“This study suggests that these mini-brain models can effectively mimic disease development and provide a potential platform for testing personalized treatments for patients,” said Dr. Zhao. says.
“Four drug candidates identified that have the potential to inhibit alpha-synuclein and restore energy production in neurons derived from LBD patients could potentially lead to the development of new treatments for LBD and related dementias in the future. may be further improved or modified.
The researchers say further research could introduce additional cell types to better mimic the complexity of the human brain. Researchers can use these enhanced models to further investigate disease mechanisms, including investigating how high-risk genes influence the development of LBD.
About this brain organoid research news
Author: Linda de Wit
Source: Mayo Clinic
Contact: Lynda De Widt – Mayo Clinic
Image: Image credited to Neuroscience News
Original research: Open access.
“Modeling Lewy body disease and identifying therapeutic agents using SNCA triple-replicated iPSC-derived cortical organoids” Scientific Advances by Na Zhao et al.
abstract
Modeling of Lewy body disease and identification of therapeutic agents using SNCA triple-replicated iPS cell-derived cortical organoids
Aggregated α-synuclein (α-SYN) protein encoded by the SNCA gene is a hallmark of Lewy body disease (LBD), which affects multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, important for LBD-associated dementia, remain unclear.
Here, we reproduced the pathology of α-SYN in cortical organoids derived from human induced pluripotent stem cells (iPSCs) generated from LBD patients with triple duplication of the SNCA gene.
Single-cell RNA sequencing combined with functional and molecular validation identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, which was confirmed at autopsy in the cortex of LBD human brains. Consistent with observations.
Additionally, we screened 1,280 Food and Drug Administration-approved drugs to inhibit α-SYN seeding activity in a real-time earthquake-induced transduction assay using the human brain, and found four candidates that inhibit α-SYN dissemination activity. The substances (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) were identified. SYN aggregation, SNCA triple duplication organoids and reduced mitochondrial dysfunction in excitatory neurons.
Our findings establish a human cortical LBD model and suggest potential therapeutics targeting α-SYN aggregation in LBD.
