Inactivation of γ-secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration.
Inactivation of γ-secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration.
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DOI：
10.15252/emmm.201707561
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发表时间：
2017-08
影响因子：
11.1
通讯作者：
De Strooper B
中科院分区：
文献类型：
--
作者：
Acx H;Serneels L;Radaelli E;Muyldermans S;Vincke C;Pepermans E;Müller U;Chávez-Gutiérrez L;De Strooper B
γ-分泌酶是膜内切割γ-酰基蛋白酶家族，是阿尔茨海默病中的重要药物靶标。在这里，我们通过删除三个前咽缺陷1（Aph 1）亚基（Aph 1abc cKO Cre +），产生了出生后前脑锥体神经元中所有γ-分泌酶缺陷的小鼠。小鼠表现出进行性皮质萎缩、神经元丢失和神经胶质增生。有趣的是，这与App，Aplp 1，Nrg 1和Dcc的膜结合片段的10倍以上积累有关，而其他已知的γ分泌酶底物如Aplp 2，Lrp 1和Sdc 3的积累程度较低。尽管有许多报告将神经变性与膜结合App片段的积累联系起来，但在联合Aph 1敲除中缺失App表达并不能挽救这种表型。重要的是，仅敲除Aph 1a-或Aph 1bc-分泌酶会导致底物的有限和差异积累。这与神经变性无关。应考虑进一步开发选择性Aph 1-γ-分泌酶抑制剂用于治疗阿尔茨海默病。
γ‐Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all γ‐secretases in the pyramidal neurons of the postnatal forebrain by deleting the three anterior pharynx defective 1 (Aph1) subunits (Aph1abc cKO Cre +). The mice show progressive cortical atrophy, neuronal loss, and gliosis. Interestingly, this is associated with more than 10‐fold accumulation of membrane‐bound fragments of App, Aplp1, Nrg1, and Dcc, while other known substrates of γ‐secretase such as Aplp2, Lrp1, and Sdc3 accumulate to lesser extents. Despite numerous reports linking neurodegeneration to accumulation of membrane‐bound App fragments, deletion of App expression in the combined Aph1 knockout does not rescue this phenotype. Importantly, knockout of only Aph1a‐ or Aph1bc‐secretases causes limited and differential accumulation of substrates. This was not associated with neurodegeneration. Further development of selective Aph1‐γ‐secretase inhibitors should be considered for treatment of Alzheimer's disease.
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影响因子：
16.2
作者：
Annaert, WG;Esselens, C;De Strooper, B
通讯作者：
De Strooper, B
DOI：
10.1073/pnas.0800507105
发表时间：
2008-07-15
影响因子：
11.1
作者：
Dejaegere, T.;Serneels, L.;De Strooper, B.
通讯作者：
De Strooper, B.
影响因子：
4.8
作者：
Gu, YJ;Chen, FS;St George-Hyslop, P
通讯作者：
St George-Hyslop, P
影响因子：
12.7
作者：
Pera M;Alcolea D;Sánchez-Valle R;Guardia-Laguarta C;Colom-Cadena M;Badiola N;Suárez-Calvet M;Lladó A;Barrera-Ocampo AA;Sepulveda-Falla D;Blesa R;Molinuevo JL;Clarimón J;Ferrer I;Gelpi E;Lleó A
通讯作者：
Lleó A
影响因子：
5.3
作者：
Mitani, Yasuyuki;Yarimizu, Junko;Matsuoka, Nobuya
通讯作者：
Matsuoka, Nobuya