1. Academic Validation
  2. Photoactivation of TGFβ/SMAD signaling pathway ameliorates adult hippocampal neurogenesis in Alzheimer's disease model

Photoactivation of TGFβ/SMAD signaling pathway ameliorates adult hippocampal neurogenesis in Alzheimer's disease model

  • Stem Cell Res Ther. 2021 Jun 11;12(1):345. doi: 10.1186/s13287-021-02399-2.
Xiaolei Wu 1 2 Qi Shen 1 2 Zhan Zhang 1 Di Zhang 2 Ying Gu 3 Da Xing 4 5
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
  • 2 Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
  • 3 Department of Laser Medicine, First Medical Center of PLA General Hospital, Beijing, 100853, China. guyinglaser301@163.com.
  • 4 MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China. xingda@scnu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China. xingda@scnu.edu.cn.
Abstract

Background: Adult hippocampal neurogenesis (AHN) is restricted under the pathological conditions of neurodegenerative diseases, especially in Alzheimer's disease (AD). The drop of AHN reduces neural circuit plasticity, resulting in the decrease of the generation of newborn neurons in dentate gyrus (DG), which makes it difficult to recover from learning/memory dysfunction in AD, therefore, it is imperative to find a therapeutic strategy to promote neurogenesis and clarify its underlying mechanism involved.

Methods: Amyloid precursor protein/presenilin 1 (APP/PS1) mice were treated with photobiomodulation therapy (PBMT) for 0.1 mW/mm2 per day in the dark for 1 month (10 min for each day). The neural stem cells (NSCs) were isolated from hippocampus of APP/PS1 transgenic mice at E14, and the cells were treated with PBMT for 0.667 mW/mm2 in the dark (5 min for each time).

Results: In this study, photobiomodulation therapy (PBMT) is found to promote AHN in APP/PS1 mice. The latent transforming growth factor-β1 (LTGFβ1) was activated in vitro and in vivo during PBMT-induced AHN, which promoted the differentiation of hippocampal APP/PS1 NSCs into newborn neurons. In particular, behavioral experiments showed that PBMT enhanced the spatial learning/memory ability of APP/PS1 mice. Mechanistically, PBMT-stimulated Reactive Oxygen Species (ROS) activates TGFβ/Smad signaling pathway to increase the interaction of the transcription factors SMAD2/3 with SMAD4 and competitively reduce the association of Smad1/5/9 with SMAD4, thereby significantly upregulating the expression of doublecortin (Dcx)/neuronal class-III β-tubulin (Tuj1) and downregulating the expression of glial fibrillary acidic protein (GFAP). These in vitro effects were abrogated when eliminating ROS. Furthermore, specific inhibition of TGFβ receptor I (TGFβR I) attenuates the DNA-binding efficiency of SMAD2/3 to the Dcx promotor triggered by PBMT.

Conclusion: Our study demonstrates that PBMT, as a viable therapeutic strategy, directs the adult hippocampal APP/PS1 NSCs differentiate towards neurons, which has great potential value for ameliorating the drop of AHN in Alzheimer's disease mice.

Keywords

Adult hippocampal neurogenesis; Alzheimer’s disease model; Neural stem cell; Newborn neuron; Photobiomodulation therapy; Spatial learning/memory ability; TGFβ/Smad pathway.

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