Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Karolinska Institutet, Stockholm, Sweden.
PLoS One. 2010 Dec 17;5(12):e15600. doi: 10.1371/journal.pone.0015600.
Cognitive impairment in Alzheimer's disease (AD) patients is associated with a decline in the levels of growth factors, impairment of axonal transport and marked degeneration of basal forebrain cholinergic neurons (BFCNs). Neurogenesis persists in the adult human brain, and the stimulation of regenerative processes in the CNS is an attractive prospect for neuroreplacement therapy in neurodegenerative diseases such as AD. Currently, it is still not clear how the pathophysiological environment in the AD brain affects stem cell biology. Previous studies investigating the effects of the β-amyloid (Aβ) peptide on neurogenesis have been inconclusive, since both neurogenic and neurotoxic effects on progenitor cell populations have been reported. In this study, we treated pluripotent human embryonic stem (hES) cells with nerve growth factor (NGF) as well as with fibrillar and oligomeric Aβ1-40 and Aβ1-42 (nM-µM concentrations) and thereafter studied the differentiation in vitro during 28-35 days. The process applied real time quantitative PCR, immunocytochemistry as well as functional studies of intracellular calcium signaling. Treatment with NGF promoted the differentiation into functionally mature BFCNs. In comparison to untreated cells, oligomeric Aβ1-40 increased the number of functional neurons, whereas oligomeric Aβ1-42 suppressed the number of functional neurons. Interestingly, oligomeric Aβ exposure did not influence the number of hES cell-derived neurons compared with untreated cells, while in contrast fibrillar Aβ1-40 and Aβ1-42 induced gliogenesis. These findings indicate that Aβ1-42 oligomers may impair the function of stem cell-derived neurons. We propose that it may be possible for future AD therapies to promote the maturation of functional stem cell-derived neurons by altering the brain microenvironment with trophic support and by targeting different aggregation forms of Aβ.
阿尔茨海默病（AD）患者的认知障碍与生长因子水平下降、轴突运输受损以及基底前脑胆碱能神经元（BFCNs）明显退化有关。在成人脑中，神经发生仍然存在，刺激中枢神经系统的再生过程是 AD 等神经退行性疾病神经替代治疗的一个有吸引力的前景。目前，AD 大脑中的病理生理环境如何影响干细胞生物学仍不清楚。先前研究β-淀粉样蛋白（Aβ）肽对神经发生的影响的研究尚无定论，因为已有报道称其对祖细胞群体具有神经生成和神经毒性作用。在这项研究中，我们用神经生长因子（NGF）以及纤维状和寡聚 Aβ1-40 和 Aβ1-42（nM-µM 浓度）处理多能人胚胎干细胞（hES），然后在体外培养 28-35 天进行分化研究。该过程应用实时定量 PCR、免疫细胞化学以及细胞内钙信号的功能研究。NGF 处理促进了向功能成熟的 BFCNs 的分化。与未处理的细胞相比，寡聚 Aβ1-40 增加了功能性神经元的数量，而寡聚 Aβ1-42 则抑制了功能性神经元的数量。有趣的是，与未处理的细胞相比，寡聚 Aβ 暴露并没有影响 hES 细胞衍生神经元的数量，而纤维状 Aβ1-40 和 Aβ1-42 则诱导神经胶质发生。这些发现表明 Aβ1-42 寡聚物可能损害干细胞衍生神经元的功能。我们提出，通过用营养支持改变大脑微环境并靶向不同聚集形式的 Aβ，未来的 AD 疗法可能能够促进功能性干细胞衍生神经元的成熟。
