BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids.
BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids.
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DOI：
10.1038/s41420-022-00845-5
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发表时间：
2022-02-02
影响因子：
7
通讯作者：
Li P
中科院分区：
文献类型：
--
作者：
Luo J;Zou H;Guo Y;Huang K;Ngan ES;Li P
β位点APP裂解酶2（BACE 2）是BACE 1的同源物，被认为是阿尔茨海默病（AD）最有希望的治疗靶点。然而，BACE 2在中枢神经系统（CNS）中的表达和功能作用仍不清楚。在此之前，我们在先天性巨结肠（HSCR）患者中鉴定了几种BACE 2罕见变异，并证明BACE 2介导的APP切割可能代表了肠神经系统HSCR发病的新机制。在这里，我们验证了这些HSCR相关的BACE 2变异体是功能缺失突变。利用人多能干细胞（hPSC）衍生的脑类器官（BO），我们进一步证明BACE 2主要在BO的脑室区和皮质板中表达，并且其表达水平随着BO的成熟而沿着逐渐增加。在功能上，我们发现与对照BO相比，携带BACE 2功能丧失突变（BACE 2G 446 R）的BO显示出更大的凋亡和增加的Aβ寡聚体水平，与AD相关表型相似。所有这些表型都可以通过去除BACE 2G 446 R BO中的APP蛋白来挽救。此外，携带APP Swedish/印第安纳州突变的BO中的BACE 2 WT过表达减弱了AD相关表型，包括Aβ蓄积和神经元细胞死亡，而不是BACE 2 G446 R。综上所述，我们的研究结果表明，BACE 2可以保护神经细胞免受Aβ积聚引起的凋亡，BACE 2介导的APP切割缺陷可能代表了HSCR和AD的共同病理机制。
β-site APP-cleaving enzyme 2 (BACE2) is a homolog of BACE1, which is considered as the most promising therapeutic target for Alzheimer’s disease (AD). However, the expression and functional role of BACE2 in central nervous system (CNS) remain obscured. Previously, we identified several BACE2 rare variants in Hirschsprung disease (HSCR) patients and proved that BACE2-mediated APP cleavage might represent a novel HSCR pathogenesis mechanism in enteric nervous system. Here, we validated that these HSCR-associated BACE2 variants were loss-of-function mutations. Using the human pluripotent stem cell (hPSC)-derived brain organoids (BOs), we further demonstrated that BACE2 was mainly expressed in the ventricular zone and cortical plate of BOs, and its expression level was gradually increased along with the BO maturation. Functionally, we found that the BOs carrying the BACE2 loss-of-function mutation (BACE2G446R) showed greater apoptosis and increased levels of Aβ oligomers compared to the control BOs, resembling with the AD-associated phenotypes. All these phenotypes could be rescued via the removal of APP protein in BACE2G446R BOs. Furthermore, rather than BACE2G446R, BACE2WT overexpression in BOs carrying the APP Swedish/Indiana mutations attenuated the AD-associated phenotypes, including Aβ accumulation and neuronal cell death. Taken together, our results unravel that BACE2 can protect the neuronal cell from apoptosis caused by Aβ accumulation, and the deficiency of BACE2-mediated APP cleavage may represent a common pathological mechanism for both HSCR and AD.
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影响因子：
11
作者：
Alić I;Goh PA;Murray A;Portelius E;Gkanatsiou E;Gough G;Mok KY;Koschut D;Brunmeir R;Yeap YJ;O'Brien NL;Groet J;Shao X;Havlicek S;Dunn NR;Kvartsberg H;Brinkmalm G;Hithersay R;Startin C;Hamburg S;Phillips M;Pervushin K;Turmaine M;Wallon D;Rovelet-Lecrux A;Soininen H;Volpi E;Martin JE;Foo JN;Becker DL;Rostagno A;Ghiso J;Krsnik Ž;Šimić G;Kostović I;Mitrečić D;LonDownS Consortium;Francis PT;Blennow K;Strydom A;Hardy J;Zetterberg H;Nižetić D
通讯作者：
Nižetić D
影响因子：
4.3
作者：
Luo J;Zou H;Deng L;Sun X;Yuan P;Li P
通讯作者：
Li P
影响因子：
15.1
作者：
Abdul-Hay SO;Sahara T;McBride M;Kang D;Leissring MA
通讯作者：
Leissring MA
影响因子：
15.3
作者：
Hu, Xiangyou;Das, Brati;Yan, Riqiang
通讯作者：
Yan, Riqiang
影响因子：
4.8
作者：
Bennett, BD;Babu-Khan, S;Vassar, R
通讯作者：
Vassar, R