Mazur-Kolecka Bozena, Frackowiak Janusz
Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Brain Res. 2006 Dec 8;1124(1):10-8. doi: 10.1016/j.brainres.2006.09.064. Epub 2006 Nov 16.
Transplantation of human neuronal progenitor cells (HNPC) is being considered for neuroreplacement therapy in beta-amyloidosis associated with neuronal loss in Down's syndrome and Alzheimer's disease. However, the influence of amyloid-beta-containing brain environment on the development of HNPCs is unknown. Recently, we demonstrated that amyloid-beta peptide (Abeta) impaired differentiation of HNPCs in culture through oxidative stress. Now we studied the effect of neprilysin, an Abeta-degrading enzyme, on development of neuronal colonies from neurospheres of HNPCs in the presence of Abeta1-40. Neprilysin increased the number of neurospheres that formed colonies of neuron-like cells. This effect of neprilysin was associated with reduced amounts of the monomeric and dimeric Abeta that remained in culture supernatants as well as the Abeta uptaken by differentiating HNPCs. Phosphoramidon, a neprilysin inhibitor, attenuated these effects of neprilysin. In control cultures of HNPCs that grew without exogenous Abeta1-40, the treatment with neprilysin reduced the number of developing colonies. This effect might result from degradation by neprilysin of endogenous Abeta produced and secreted by HNPCs or other peptides that are involved in neuronal development. The results demonstrate that even a partial reduction of extracellular Abeta levels by neprilysin may facilitate development of HNPCs into neurons in an environment overloaded with Abeta. This finding suggests that neprilysin could facilitate neuroreplacement therapy with HNPCs in treatment of neurodegenerative diseases.
人类神经祖细胞（HNPC）移植正被考虑用于唐氏综合征和阿尔茨海默病中与神经元丢失相关的β-淀粉样变性的神经替代治疗。然而，含β-淀粉样蛋白的脑环境对HNPC发育的影响尚不清楚。最近，我们证明β-淀粉样肽（Aβ）通过氧化应激损害培养中的HNPC分化。现在我们研究了中性内肽酶（一种Aβ降解酶）在Aβ1-40存在的情况下对HNPC神经球形成神经元集落发育的影响。中性内肽酶增加了形成神经元样细胞集落的神经球数量。中性内肽酶的这种作用与培养上清液中残留的单体和二聚体Aβ以及分化的HNPC摄取的Aβ量减少有关。中性内肽酶抑制剂磷酰胺减弱了中性内肽酶的这些作用。在没有外源性Aβ1-40生长的HNPC对照培养物中，用中性内肽酶处理减少了发育中的集落数量。这种作用可能是由于中性内肽酶对HNPC产生和分泌的内源性Aβ或参与神经元发育的其他肽的降解所致。结果表明，即使中性内肽酶使细胞外Aβ水平部分降低，也可能在Aβ过载环境中促进HNPC向神经元的发育。这一发现表明，中性内肽酶在神经退行性疾病治疗中可能有助于用HNPC进行神经替代治疗。
