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与家族性阿尔茨海默病相关的PSEN1突变通过增加的Notch信号影响神经发育

Erin M Hurley¹, Pawel Mozolewski², Radek Dobrowolski³

¹Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas San Antonio, San Antonio, TX 78249, USA; Brain Health Consortium, The University of Texas San Antonio, San Antonio, TX 78249, USA.

Stem cell reports

|June 23, 2023

概括

家庭性阿尔茨海默病 (fAD) 突变在PSEN1中破坏了人类皮质球体的早期大脑发育. 这项研究揭示了特定突变如何影响神经发育,为早期的fAD治疗提供了新的见解.

科学领域:

神经科学是一个神经科学.
发展生物学发展生物学
遗传学是一个遗传学.

背景情况:

阿尔茨海默病 (AD) 是一种常见的神经退行性疾病.
PSEN1突变是家族性AD (fAD) 的主要原因.
神经发育障碍可能是AD病原体的基础.

研究的目的:

研究一种特定的PSEN1突变 (L435F) 对人类大脑发育的影响.
利用人类皮层球体 (hCSs) 来建模fAD早期神经发育变化.
了解PSEN1突变如何影响Notch信号和神经元分化.

主要方法:

人类诱导的多能干细胞干细胞衍生的皮质球体 (hCSs) 的生成.
对hCS发育的分析,包括大小,祖细胞增殖和神经元分化.
对诺奇标基因表达和粉样β (Aβ) 表达的评估.
在晚期hCSs中监测神经元活动.

主要成果:

该PSEN1 L435F突变增加了hCS大小和原始神经元数量,同时减少了神经元转移后的数量.
在早期hCS发育过程中观察到高Notch目标基因表达.
在hCS晚期阶段检测到Aβ表达和神经元活动的改变.
这些发现与之前的研究有所不同,表明突变特异性影响.

结论:

特定的PSEN1突变可以显著改变人类的神经发育.
由PSEN1突变驱动的早期细胞变化可能导致fAD进展.
hCS模型为研究fAD的发育起源提供了一个平台.
了解这些早期变化可能会导致对fAD的早期治疗干预.

关键词:

阿尔茨海默氏症是阿尔茨海默氏症的一种疾病.在NOTCH信号中发出信号.在PSEN1上.人类皮层球形状物这就是 iPSC 的意义.神经退行症的神经退行症神经发育的神经发育有机体有机体是有机的有机物 γ-秘密的秘密

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