Inhibition of APP gamma-secretase restores Sonic Hedgehog signaling and neurogenesis in the Ts65Dn mouse model of Down syndrome.
Inhibition of APP gamma-secretase restores Sonic Hedgehog signaling and neurogenesis in the Ts65Dn mouse model of Down syndrome.
复制标题
DOI：
10.1016/j.nbd.2015.08.001
复制
发表时间：
2015-10
影响因子：
6.1
通讯作者：
Bartesaghi R
中科院分区：
文献类型：
--
作者：
Giacomini A;Stagni F;Trazzi S;Guidi S;Emili M;Brigham E;Ciani E;Bartesaghi R
唐氏综合征（Down syndrome，DS）患者早期发育阶段的神经发生障碍是导致智力障碍的关键因素。先前的证据提供了神经发生障碍和有丝分裂Sonic Hedgehog（Shh）通路故障之间的因果关系。特别是，AICD（淀粉样前体蛋白胞内结构域），三体基因APP（淀粉样前体蛋白）的切割产物的过量水平上调Ptch 1（Patched 1）的转录，Shh受体保持抑制途径。由于AICD是由γ-分泌酶裂解APP产生的，因此本研究的目的是确定用γ-分泌酶抑制剂治疗是否使AICD水平正常化并恢复三体神经前体细胞中的神经发生。我们发现，用选择性γ-分泌酶抑制剂（ELND 006; ELN）处理恢复了源自DS的Ts 65 Dn小鼠模型的脑室下区（SVZ）的神经球的增殖。这种作用伴随着AICD和Ptch 1水平的降低，并通过用环巴胺抑制Shh通路来防止。在出生后P3-P15用ELN处理Ts 65 Dn小鼠恢复了SVZ和海马的神经发生、海马颗粒细胞数量和突触发育，表明处理对脑发育有积极影响。此外，在经治疗的Ts 65 Dn小鼠的海马中，由AICD转录调节的各种基因的表达水平降低，包括APP，其起源底物。γ-分泌酶抑制剂目前被设想为治疗阿尔茨海默病的工具，因为它们降低β淀粉样蛋白水平。目前的研究结果提供了新的证据，γ-分泌酶抑制剂可能是一种策略，拯救神经发生缺陷的DS。促有丝分裂Shh通路紊乱减少唐氏综合征（DS）的神经发生。APP三倍化导致其裂解产物AICD的过度形成。AICD导致Ptch 1的过度转录，Ptch 1是Shh通路的阻遏物。ELND 006是一种γ分泌酶抑制剂，可降低AICD水平和Ptch 1表达。ELND 006治疗可恢复DS Ts 65 Dn小鼠模型的神经发生。
Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3–P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower βamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS. Derangement of the mitogenic Shh pathway reduces neurogenesis in Down syndrome (DS). APP triplication causes excessive formation of its cleavage products AICD. AICD causes excessive transcription of Ptch1, the repressor of the Shh pathway. ELND006, a gamma secretase inhibitor, reduces AICD levels and Ptch1 expression. Treatment with ELND006 restores neurogenesis in the Ts65Dn mouse model of DS.