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Proinflammatory S100A9 Regulate Differentiation and Aggregation of Neural Stem Cells

By Yin Tian, Rui Cao, Bingchen Che, Yong Tang, Lin Jiang, Bai Qiao, Yonggang Liu, Ludmilla A Morozovaroche, Ce Zhang

Posted 07 Jun 2020
bioRxiv DOI: 10.1101/2020.06.06.137745

Inflammation is the primary pathological feature of neurodegenerative diseases such as Alzheimers (AD) and Parkinsons disease. Proinflammatory molecules (e.g. S100A9) play important roles during progression of the diseases by regulating behavior and fate of multiple cell types in the nervous system (1). Our earlier studies reveal that S100A9 is toxic to neurons, and its interaction with Abeta peptides leads to the formation of large non-toxic amyloidogenic aggregates, suggesting a protective role of Abeta amyloids (2). We herein, demonstrate that S100A9 interacts with neural stem cells (NSCs) and causes NSC differentiation. In the brain of transgenic AD mouse models, we found large quantities of proinflammatory S100A9, which colocalizes with the differentiated NSCs. NSC sphere formation, which is a representative character of NSC stemness, is also substantially inhibited by S100A9. These results suggest that S100A9 is a representative marker for the inflammatory conditions in AD, and it promotes NSC differentiation. Intriguingly, in contrast to the death of both stem and differentiated NSCs caused by high S100A9 doses, S100A9 at a moderate concentration is toxic only to the early differentiated NSCs (i.e. progenitor cells and immature neurons), but not the stem cells. We therefore postulate that at the early stage of AD, expression of S100A9 leads to NSC differentiation, which remedies the neuron damages. The application drugs, which help maintain NSC stemness (e.g. PDGF), may help overcome the acute inflammatory conditions and improve the efficacy of NSC transplantation therapy. ### Competing Interest Statement The authors have declared no competing interest.

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