Study summary · research use only
Thymosin beta 4 as an Alzheimer disease intervention target identified using human brain organoids
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study used cerebral organoids derived from human induced pluripotent stem cells (iPSCs) carrying amyloid precursor protein (APP) mutations linked to familial Alzheimer disease (fAD), alongside 5xfAD model mice, to examine thymosin beta 4 (Tβ4). Mature neurons were decreased in fAD organoids compared with healthy controls, accompanied by increased cell senescence and β-amyloid (Aβ) production, and expression of the gene TMSB4X (encoding Tβ4) was significantly decreased in fAD organoid neurons and in excitatory neurons from Alzheimer disease patients. Treatment with Tβ4 was reported to rescue the neurodevelopmental deficits and Aβ formation seen in fAD organoids, with similar reported effects in 5xfAD model mice.
Abstract
The developmental origin of Alzheimer disease (AD) has been proposed but is arguably debated. Here, we developed cerebral organoids from induced pluripotent stem cells (iPSCs) with mutations in amyloid precursor protein (APP) associated with familial AD (fAD) and analyzed the dynamic changes of cellular states. We found that mature neurons induced in fAD organoids markedly decreased compared to that of health control, accompanied with increased cell senescence and β-amyloid (Aβ) production. Interestingly, the expression level of the gene TMSB4X that encodes thymosin beta 4 (Tβ4) significantly decreased both in fAD organoids' neurons and AD patients' excitatory neurons. Remarkably, the neurodevelopmental deficits and Aβ formation in fAD organoids were rescued by treatment with Tβ4. The beneficial effects of Tβ4 were also revealed in 5xfAD model mice. Thus, this study has identified Tβ4 as a neuroprotective factor that may mitigate altered neurogenesis and AD pathology, highlighting a potential for disease intervention.
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