Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis.
Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis.
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DOI：
10.1016/j.celrep.2020.108615
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发表时间：
2021-01-12
期刊：
影响因子：
8.8
通讯作者：
Wray S
中科院分区：
文献类型：
--
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
早老素1 （PSEN1）或早老素2 （PSEN2）是γ-分泌酶的催化亚基，其突变可导致家族性阿尔茨海默病（fAD）。我们假设PSEN1的突变减少了Notch信号并改变了神经发生。发育和成人神经发生的表达数据显示，Notch和γ-分泌酶在干细胞中表达相对富集，而APP和β-分泌酶在神经元中表达富集。我们使用两个正交系统：2D的皮质分化和3D的脑类器官生成，观察含有PSEN1突变的fAD iPSCs的过早神经发生。这部分是由于Notch信号减少所致。我们将这些研究扩展到突变确认的死后组织中的成年海马神经发生。fAD病例显示突变特异性效应和新生神经元丰度减少的趋势，支持过早衰老表型。总之，这些结果支持fAD突变导致的神经发生改变，并表明神经干细胞生物学在衰老和疾病中受到影响。在神经发生中，PSEN1在祖细胞中表达丰富，就像在神经元中表达APP一样，抑制β-分泌酶对神经发生的影响很小，与γ-分泌酶相反家族性阿尔茨海默病PSEN1突变导致过早的神经发生家族性阿尔茨海默病死后海马中新生神经元减少的趋势Arber等人利用人类iPSC神经发生模拟成人海马神经发生，研究家族性阿尔茨海默病（fAD）突变。与APP相比，PSEN1和γ-分泌酶成分在神经祖细胞中富集，突变驱动过早的神经发生。死后海马体显示出相应的神经发生改变趋势。
Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer’s disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease. In neurogenesis, PSEN1 expression is enriched in progenitors, as it is for APP in neurons Inhibiting β-secretase has little effect on neurogenesis, contrary to γ-secretase Familial Alzheimer’s disease mutations in PSEN1 cause premature neurogenesis Trend toward fewer newborn neurons in familial AD postmortem hippocampi Arber et al. employ human iPSC neurogenesis to model adult hippocampal neurogenesis, investigating familial Alzheimer’s disease (fAD) mutations. In contrast to APP, PSEN1 and γ-secretase components are enriched in neural progenitors and mutations drive premature neurogenesis. Postmortem fAD hippocampi show corresponding trends toward altered neurogenesis.
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影响因子：
11
作者：
Arber C;Toombs J;Lovejoy C;Ryan NS;Paterson RW;Willumsen N;Gkanatsiou E;Portelius E;Blennow K;Heslegrave A;Schott JM;Hardy J;Lashley T;Fox NC;Zetterberg H;Wray S
通讯作者：
Wray S
影响因子：
3.4
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Tanzi RE
影响因子：
4.6
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Briley D;Ghirardi V;Woltjer R;Renck A;Zolochevska O;Taglialatela G;Micci MA
通讯作者：
Micci MA
影响因子：
23.9
作者：
Encinas, Juan M.;Michurina, Tatyana V.;Peunova, Natalia;Park, June-Hee;Tordo, Julie;Peterson, Daniel A.;Fishell, Gord;Koulakov, Alex;Enikolopov, Grigori
通讯作者：
Enikolopov, Grigori
影响因子：
4.6
作者：
Bergström P;Agholme L;Nazir FH;Satir TM;Toombs J;Wellington H;Strandberg J;Bontell TO;Kvartsberg H;Holmström M;Boreström C;Simonsson S;Kunath T;Lindahl A;Blennow K;Hanse E;Portelius E;Wray S;Zetterberg H
通讯作者：
Zetterberg H