BACKGROUND Alzheimer's disease (AD) is an inexorable neurodegenerative disease that commonly occurs in the elderly. The cognitive impairment caused by AD is associated with abnormal accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, which are accompanied by inflammation. Neural stem cells (NSCs) are self-renewing, multipotential cells that differentiate into distinct neural cells. When transplanted into a diseased brain, NSCs repair and replace injured tissues after migration toward and engraftment within lesions. We investigated the therapeutic effects in an AD mouse model of human NSCs (hNSCs) that derived from an aborted human fetal telencephalon at 13 weeks of gestation. Cells were transplanted into the cerebral lateral ventricles of neuron-specific enolase promoter-controlled APPsw-expressing (NSE/APPsw) transgenic mice at 13 months of age. RESULTS Implanted cells extensively migrated and engrafted, and some differentiated into neuronal and glial cells, although most hNSCs remained immature. The hNSC transplantation improved spatial memory in these mice, which also showed decreased tau phosphorylation and Aβ42 levels and attenuated microgliosis and astrogliosis. The hNSC transplantation reduced tau phosphorylation via Trk-dependent Akt/GSK3β signaling, down-regulated Aβ production through an Akt/GSK3β signaling-mediated decrease in BACE1, and decreased expression of inflammatory mediators through deactivation of microglia that was mediated by cell-to-cell contact, secretion of anti-inflammatory factors generated from hNSCs, or both. The hNSC transplantation also facilitated synaptic plasticity and anti-apoptotic function via trophic supplies. Furthermore, the safety and feasibility of hNSC transplantation are supported. CONCLUSIONS These findings demonstrate the hNSC transplantation modulates diverse AD pathologies and rescue impaired memory via multiple mechanisms in an AD model. Thus, our data provide tangible preclinical evidence that human NSC transplantation could be a safe and versatile approach for treating AD patients.

中文翻译：

---

人类神经干细胞可减轻小鼠模型中的阿尔茨海默氏病样病理。

背景技术阿尔茨海默氏病（AD）是一种不可避免的神经退行性疾病，通常发生在老年人中。AD引起的认知障碍与β-淀粉样蛋白（Aβ）和磷酸化tau蛋白的异常积累有关，并伴有炎症。神经干细胞（NSC）是自我更新的多能细胞，可分化为不同的神经细胞。当移植到患病的大脑中时，NSC在向病灶迁移并植入病灶后修复并替换受伤的组织。我们调查了人类NSCs（hNSCs）的AD小鼠模型中的治疗效果，该模型源自妊娠13周流产的人类胎儿端脑。将细胞移植到13个月大的神经元特异性烯醇酶启动子控制的APPsw表达（NSE / APPsw）转基因小鼠的脑侧脑室。结果尽管大多数hNSC仍未成熟，但植入的细胞广泛迁移和移植，并分化为神经元和神经胶质细胞。hNSC移植改善了这些小鼠的空间记忆，还显示出降低的tau磷酸化和Aβ42水平，并减轻了小胶质细胞增生和星形胶质细胞增生。hNSC移植通过Trk依赖性Akt /GSK3β信号传导减少tau磷酸化，通过Akt /GSK3β信号传导介导的BACE1减少而下调Aβ产生，并通过使小胶质细胞失活来介导细胞间介导的小胶质细胞减少炎症介质的表达。细胞接触 hNSC产生的抗炎因子的分泌，或两者兼而有之。hNSC移植还通过营养供应促进了突触可塑性和抗凋亡功能。此外，还支持了hNSC移植的安全性和可行性。结论这些发现表明，hNSC移植可通过AD模型中的多种机制调节多种AD病理并挽救受损的记忆。因此，我们的数据提供了明显的临床前证据，即人类NSC移植可能是治疗AD患者的安全且通用的方法。结论这些发现表明，hNSC移植可通过AD模型中的多种机制调节多种AD病理并挽救受损的记忆。因此，我们的数据提供了明显的临床前证据，即人类NSC移植可能是治疗AD患者的安全且通用的方法。结论这些发现表明，hNSC移植可通过AD模型中的多种机制调节多种AD病理并挽救受损的记忆。因此，我们的数据提供了明显的临床前证据，即人类NSC移植可能是治疗AD患者的安全且通用的方法。