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Researchers at ShanghaiTech University in China have discovered a promising new treatment target for Alzheimer’s disease and gained a better understanding of the disease pathology with the help of specially designed brain organoids.
As the most common form of dementia, Alzheimer’s disease is a progressive neurodegenerative condition characterized by the loss of memory and thinking skills, and eventually, the ability to perform simple, everyday tasks. Alzheimer’s disease accounts for 60-70% of all dementia cases, affecting approximately one in 20 people aged 65 or older.
While substantial research goes into understanding Alzheimer’s disease, the developmental origin and causes of the condition are still widely debated. In their study, published in the journal Stem Cell Reports and titled “Thymosin Beta 4 as an Alzheimer Disease Intervention Target Identified Using Human Brain Organoids,” the researchers therefore wanted to understand the changes that happen early on in the brains of people with Alzheimer’s disease.
The team used brain organoids that could model the characteristics of early human brain development and function. They specifically focused on familial Alzheimer’s disease (fAD), a rarer form of the condition that is inherited through known genetic mutations.
To develop brain organoids that model fAD, the researchers used induced pluripotent stem cells with mutations in the amyloid precursor protein. They then compared the neural development and genetics in these organoids with organoids modeling healthy brains using RNA sequencing. They also compared their results with postmortem brain samples from persons who had had fAD to validate their findings.
The researchers found that fAD organoids had elevated levels of β-amyloid (Aβ) peptides, supporting one of the main hypotheses of the condition, in which it is believed that the accumulation of Aβ proteins in the brain cause Alzheimer’s disease.
Moreover, fAD organoids showed that the number of mature neurons significantly decreased compared to healthy brains, and fAD organoids also had higher levels of cell senescence and cell death compared to the healthy control organoids.
A key finding of the study was that the gene expression of a gene called TMSB4X, which encodes a peptide called thymosin beta 4 (Tβ4), was significantly downregulated in the neurons of fAD organoids and the excitatory neurons of Alzheimer’s disease patients.
Lastly, the research team treated fAD organoids with Tβ4 and also tested it in a mouse model with the same condition. They found that treatment with Tβ4 could “rescue” the neurodevelopmental deficits and Aβ formation both in the mouse model and organoids with fAD.
“[…] This study has identified Tβ4 as a neuroprotective factor that may mitigate altered neurogenesis and [Alzheimer’s disease] pathology, highlighting a potential for disease intervention,” the researchers wrote in their paper, adding: “Thus, the fAD organoids developed in this study have shown early onset of neurogenesis defects and provided a platform for target screening and testing.”