MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
J Neuroinflammation. 2022 Oct 10;19(1):253. doi: 10.1186/s12974-022-02617-5.
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.
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 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 (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.
Our results showed that PBMT treatment could promote AHN and reverse cognitive deficits in AD mouse model. The expression of interferon-γ (IFN-γ) 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-β1 (TGFβ1)/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 β-tubulin (Tuj1) and postsynaptic density protein 95 (PSD95), but the effects of PBMT was blocked by reactive oxygen species (ROS) scavenger or JAK2 inhibitor.
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-γ/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.
免疫系统与突触可塑性、炎症和阿尔茨海默病（AD）的进展有关。然而，很少有研究通过调节非实质免疫细胞的功能来改善 AD 患者大脑中神经干细胞（NSC）的龛位微环境，以促进成年海马神经发生（AHN）。
用光生物调节疗法（PBMT）对 APP/PS1 和 3xTg（APP/PS1/tau）AD 模型的淋巴结进行 10J/cm，每天 1 次，共 1 个月（每天 10 分钟）处理，用 PBMT 处理从这两种 AD 模型中分离出的 T 淋巴细胞，剂量为 2J/cm（每次 5 分钟）。用 PBMT 处理来自这两种 AD 模型的 E14 海马的 NSCs，将 PBMT 处理过的 T 淋巴细胞条件培养基与 NSCs 共培养以促进 NSCs 分化。
我们的结果表明，PBMT 治疗可促进 AHN，并逆转 AD 模型的认知障碍。在 PBMT 治疗后，这两种 AD 模型的大脑中干扰素-γ（IFN-γ）和白细胞介素-10（IL-10）的表达上调，这是由 Janus 激酶 2（JAK2）介导的信号转导和转录激活因子 4（STAT4）/STAT5 信号通路在 CD4 T 细胞中的激活诱导的。此外，还检测到大脑中 CD4 T 细胞水平升高和转化生长因子-β1（TGFβ1）/胰岛素样生长因子-1（IGF-1）/脑源性神经营养因子（BDNF）蛋白表达水平升高。更重要的是，与 PBMT 处理的 T 淋巴细胞条件培养基共培养的源自这两种 AD 模型的 NSCs 显示出促进 NSCs 分化的作用，这反映在神经元 III 类 β-微管蛋白（Tuj1）和突触后密度蛋白 95（PSD95）的表达上调，但 PBMT 的作用被活性氧（ROS）清除剂或 JAK2 抑制剂阻断。
我们的研究表明，PBMT 通过激活 JAK2/STAT4/STAT5 信号通路，促进非实质 CD4 T 细胞中 IFN-γ/IL-10 的表达，诱导改善大脑微环境条件，并减轻 APP/PS1 和 3xTg-AD 小鼠模型的认知障碍，从而发挥有益的神经发生调节作用。
