Familial Alzheimer's disease-associated PSEN1 mutations affect neurodevelopment through increased Notch signaling.
Familial Alzheimer's disease-associated PSEN1 mutations affect neurodevelopment through increased Notch signaling.
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DOI：
10.1016/j.stemcr.2023.05.018
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发表时间：
2023-07-11
影响因子：
5.9
通讯作者：
Hsieh, Jenny
中科院分区：
文献类型：
--
作者：
Hurley, Erin M.;Mozolewski, Pawel;Dobrowolski, Radek;Hsieh, Jenny
阿尔茨海默病（AD）是最常见的神经退行性疾病，但其根本原因可能在于神经发育。PSEN 1突变导致大多数家族性AD，可能是通过破坏适当的Notch信号传导，引起早期未被注意的细胞变化，影响后期AD进展。虽然啮齿动物模型可用于AD后期的建模，但人诱导多能干细胞衍生的皮质球状体（hCS）允许在发育过程中在细胞水平上研究人皮质。在这里，我们表明，PSEN 1 L435 F杂合突变影响hCS的发展，增加大小，增加祖细胞，并减少有丝分裂后神经元作为一个结果，增加Notch靶基因表达在早期hCS发展。我们还发现在hCS后期Aβ表达和神经元活性发生改变。这些结果与之前的研究结果形成对比，显示了单个PSEN 1突变如何不同地影响神经发育，并可能深入了解fAD的进展，从而为更有效的治疗提供更早的时间点。PSEN 1 L435 F影响皮质球状体生长和形态PSEN 1 L435 F增加皮质祖细胞并减少神经元分化特异性Notch 1抑制拯救细胞表型PSEN 1 L435 F增加Aβ42/40和Aβ43/40比率Hsieh和同事发现阿尔茨海默病相关的早老蛋白1 L435 F突变导致hiPSC衍生的3D皮质球状体中Notch信号传导增加。他们发现PSEN 1 hCS的大小和形态改变，神经元分化减少，Notch靶基因表达增加。Notch 1抑制挽救了表型。作者还发现Aβ42/40和Aβ43/40增加，这表明神经发育的改变可能在阿尔茨海默病的病理学中起作用。
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, but its root cause may lie in neurodevelopment. PSEN1 mutations cause the majority of familial AD, potentially by disrupting proper Notch signaling, causing early unnoticed cellular changes that affect later AD progression. While rodent models are useful for modeling later stages of AD, human induced pluripotent stem cell-derived cortical spheroids (hCSs) allow access to studying the human cortex at the cellular level over the course of development. Here, we show that the PSEN1 L435F heterozygous mutation affects hCS development, increasing size, increasing progenitors, and decreasing post-mitotic neurons as a result of increased Notch target gene expression during early hCS development. We also show altered Aβ expression and neuronal activity at later hCS stages. These results contrast previous findings, showing how individual PSEN1 mutations may differentially affect neurodevelopment and may give insight into fAD progression to provide earlier time points for more effective treatments. PSEN1 L435F affects cortical spheroid growth and morphology PSEN1 L435F increases cortical progenitors and reduces neuron differentiation Specific Notch1 inhibition rescues cellular phenotypes PSEN1 L435F increases Aβ42/40 and Aβ43/40 ratios Hsieh and colleagues found the Alzheimer’s-related Presenilin1 L435F mutation causes increased Notch signaling in hiPSC-derived 3D cortical spheroids. They found altered size and morphology of PSEN1 hCSs, reduced neuronal differentiation, and increased Notch target gene expression. Phenotypes were rescued with Notch1 inhibition. The authors also found increased Aβ42/40 and Aβ43/40, suggesting that altered neurodevelopment may play a role in Alzheimer’s pathology.
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影响因子：
29
作者：
Quiroz YT;Schultz AP;Chen K;Protas HD;Brickhouse M;Fleisher AS;Langbaum JB;Thiyyagura P;Fagan AM;Shah AR;Muniz M;Arboleda-Velasquez JF;Munoz C;Garcia G;Acosta-Baena N;Giraldo M;Tirado V;Ramírez DL;Tariot PN;Dickerson BC;Sperling RA;Lopera F;Reiman EM
通讯作者：
Reiman EM
影响因子：
8.8
作者：
Arber C;Lovejoy C;Harris L;Willumsen N;Alatza A;Casey JM;Lines G;Kerins C;Mueller AK;Zetterberg H;Hardy J;Ryan NS;Fox NC;Lashley T;Wray S
通讯作者：
Wray S
影响因子：
5.4
作者：
De Strooper, Bart;Iwatsubo, Takeshi;Wolfe, Michael S.
通讯作者：
Wolfe, Michael S.
影响因子：
6
作者：
Bussière, T;Bard, F;Buttini, M
通讯作者：
Buttini, M
影响因子：
5.7
作者：
Kennedy, Kristen M.;Rodrigue, Karen M.;Devous, Michael D., Sr.;Hebrank, Andrew C.;Bischof, Gerard N.;Park, Denise C.
通讯作者：
Park, Denise C.