PDF(Pubmed)
Abstract：
Stem-cell-based therapy is very promising for Alzheimer\'s disease (AD), yet has not become a reality. A critical challenge is the transplantation microenvironment, which impacts the therapeutic effect of stem cells. In AD brains, amyloid-beta (Aβ) peptides and inflammatory cytokines continuously poison the tissue microenvironment, leading to low survival of grafted cells and restricted efficacy. It is necessary to create a growth-supporting microenvironment for transplanted cells. Recent advances in AD studies suggest that the asparaginyl endopeptidase (AEP) is a potential intervention target for modifying pathological changes. We here chose APP/PS1 mice as an AD model and employed pharmacological inhibition of the AEP for one month to improve the brain microenvironment. Thereafter, we transplanted neural stem cells (NSCs) into the hippocampus and maintained therapy for one more month. We found that inhibition of AEPs resulted in a significant decrease of Aβ, TNF-α, IL-6 and IL-1β in their brains. In AD mice receiving NSC transplantation alone, the survival of NSCs was at a low level, while in combination with AEP inhibition pre-treatment the survival rate of engrafted cells was doubled. Within the 2-month treatment period, implantation of NSCs plus pre-inhibition of the AEP significantly enhanced neural plasticity of the hippocampus and rescued cognitive impairment. Neither NSC transplantation alone nor AEP inhibition alone achieved significant efficacy. In conclusion, pharmacological inhibition of the AEP ameliorated brain microenvironment of AD mice, and thus improved the survival and therapeutic efficacy of transplanted stem cells.
摘要：
干细胞为基础的治疗是非常有前途的阿尔茨海默病（AD），但还没有成为现实。一个关键的挑战是移植微环境，影响干细胞的治疗效果。在AD大脑中，淀粉样β（Aβ）肽和炎症细胞因子持续毒害组织微环境，导致移植细胞的低存活率和有限的功效。有必要为移植细胞创建支持生长的微环境。AD研究的最新进展表明，天冬酰胺酰内肽酶（AEP）是修饰病理变化的潜在干预靶标。我们在这里选择APP/PS1小鼠作为AD模型，并采用AEP的药理学抑制一个月来改善大脑微环境。此后,我们将神经干细胞（NSC）移植到海马中，并维持治疗一个月。我们发现AEPs的抑制导致Aβ的显著降低,TNF-α,他们大脑中的IL-6和IL-1β。在仅接受NSC移植的AD小鼠中，神经干细胞的存活率很低，而与AEP抑制预处理组合,移植细胞的存活率加倍。在2个月的治疗期内，神经干细胞的植入和AEP的预抑制显著增强了海马的神经可塑性并挽救了认知障碍。单独的NSC移植或单独的AEP抑制均未达到显著功效。总之,药物抑制AEP改善AD小鼠的大脑微环境，从而提高了移植干细胞的存活率和治疗效果。
