APP-dependent alteration of GSK3 beta activity impairs neurogenesis in the Ts65Dn mouse model of Down syndrome

作者：Trazzi Stefania; Fuchs Claudia; De Franceschi Marianna; Mitrugno Valentina Maria; Bartesaghi Renata; Ciani Elisabetta^*

来源：Neurobiology of Disease, 2014, 67: 24-36.

DOI：10.1016/j.nbd.2014.03.003

• Down syndrome
• Neurogenesis impairment
• GSK3 beta
• APP
• AICD
• 5-HT1A receptor
• Fluoxetine
• Lithium

Intellectual disability in Down syndrome (DS) appears to be related to severe neurogenesis impairment during brain development. The molecular mechanisms underlying this defect are still largely unknown. Accumulating evidence has highlighted the importance of GSK3 beta signaling for neuronal precursor proliferation/differentiation. In neural precursor cells (NPCs) from Ts65Dn mice and human fetuses with DS, we found reduced GSK3 beta phosphorylation and, hence, increased GSK3 beta activity. In cultures of trisomic subventricular-zone-derived adult NPCs (aNPCs) we found that deregulation of GSK3 beta activity was due to higher levels of the AICD fragment of the trisomic gene APP that directly bound to GSK3 beta. We restored GSK3 beta phosphorylation in trisomic aNPCs using either lithium, a well-known GSK3 beta inhibitor, or using a 5-HT receptor agonist or fluoxetine, which activated the serotonin receptor 5-HT1A. Importantly, this effect was accompanied by restoration of proliferation, cell fate specification and neuronal maturation. In agreement with results obtained in vitro, we found that early treatment with fluoxetine, which was previously shown to rescue neurogenesis and behavior in Ts65Dn mice, restored GSK3 beta phosphorylation. These results provide a link between GSK3 beta activity alteration, APP triplication and the defective neuronal production that characterizes the DS brain. Knowledge of the molecular mechanisms underlying neurogenesis alterations in DS may help to devise therapeutic strategies, potentially usable in humans. Results suggest that drugs that increase GSK3 beta phosphorylation, such as lithium or fluoxetine, may represent useful tools for the improvement of neurogenesis in DS.

• 出版日期2014-7