Enhanced differentiation of neural progenitor cells in Alzheimer's disease into vulnerable immature neurons

iScience. 2025 Apr 16;28(5):112446. doi: 10.1016/j.isci.2025.112446. eCollection 2025 May 16.

ABSTRACT

Focusing on the early stages of Alzheimer's disease (AD) holds great promise. However, the specific events in neural cells preceding AD onset remain elusive. To address this, we utilized human-induced pluripotent stem cells carrying APPswe mutation to explore the initial changes associated with AD progression. We observed enhanced neural activity and early neuronal differentiation in APPswe cerebral organoids cultured for one month. This phenomenon was also evident when neural progenitor cells (NPCs) were differentiated into neurons. Furthermore, transcriptomic analyses of NPCs and neurons confirmed altered expression of neurogenesis-related genes in APPswe NPCs. We also found that the upregulation of reactive oxygen species (ROS) is crucial for early neuronal differentiation in these cells. In addition, APPswe neurons remained immature after initial differentiation with increased susceptibility to toxicity, providing valuable insights into the premature exit from the neural progenitor state and the increased vulnerability of neural cells in AD.

PMID:40384927 | PMC:PMC12084003 | DOI:10.1016/j.isci.2025.112446