Promoted CD4+ T cell-derived IFN-γ/IL-10 by photobiomodulation therapy modulates neurogenesis to ameliorate cognitive deficits in APP/PS1 and 3xTg-AD mice

Background The immune system has been implicated in synaptic plasticity, inflammation, and the progression of Alzheimer's disease (AD). However, there were few studies on improving the niche microenvironment of neural stem cells (NSCs) in the brain of AD to promote adult hippocampal neurogenesis (AHN) by regulating the function of non-parenchymal immune cells. Methods The lymph nodes of amyloid precursor protein/presenilin 1 (APP/PS1) and 3xTg (APP/PS1/tau) mouse models of AD were treated with photobiomodulation therapy (PBMT) for 10 J/cm(2) per day for 1 month (10 min for each day), T lymphocytes isolated from these two AD models were treated with PBMT for 2 J/cm(2) (5 min for each time). The NSCs isolated from hippocampus of these two AD models at E14, and the cells were co-cultivated with PBMT-treated T lymphocyte conditioned medium for NSCs differentiation. Results Our results showed that PBMT treatment could promote AHN and reverse cognitive deficits in AD mouse model. The expression of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) was upregulated in the brain of these two AD models after PBMT treated, which was induced by the activation of Janus kinase 2 (JAK2)-mediated signal transducer and activator of transcription 4 (STAT4)/STAT5 signaling pathway in CD4(+) T cells. In addition, elevated CD4(+) T cell levels and upregulated transforming growth factor-beta 1 (TGF beta 1)/insulin-like growth factors-1 (IGF-1)/brain-derived neurotrophic factor (BDNF) protein expression levels were also detected in the brain. More importantly, co-cultivated the PBMT-treated T lymphocyte conditioned medium with NSCs derived from these two AD models was shown to promote NSCs differentiation, which was reflected in the upregulation of both neuronal class-III beta-tubulin (Tuj1) and postsynaptic density protein 95 (PSD95), but the effects of PBMT was blocked by reactive oxygen species (ROS) scavenger or JAK2 inhibitor. Conclusion Our research suggests that PBMT exerts a beneficial neurogenesis modulatory effect through activating the JAK2/STAT4/STAT5 signaling pathway to promote the expression of IFN-gamma/IL-10 in non-parenchymal CD4(+) T cells, induction of improvement of brain microenvironmental conditions and alleviation of cognitive deficits in APP/PS1 and 3xTg-AD mouse models.

Automated summary

This study demonstrated that photobiomodulation therapy (PBMT) effectively promotes adult hippocampal neurogenesis (AHN) and reverses cognitive deficits in AD mouse models by upregulating expression of interferon-gamma (IFN-γ) and interleukin-10 (IL-10) in non-parenchymal CD4(+) T cells through the JAK2/STAT4/STAT5 signaling pathway.