BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids
Abstract 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 BACE...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-022-00845-5 |
| _version_ | 1798023851625414656 |
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| author | Juan Luo Hailin Zou Yibo Guo Ke Huang Elly Sau-Wai Ngan Peng Li |
| author_facet | Juan Luo Hailin Zou Yibo Guo Ke Huang Elly Sau-Wai Ngan Peng Li |
| author_sort | Juan Luo |
| collection | DOAJ |
| description | Abstract 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 (BACE2 G446R ) 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 BACE2 G446R BOs. Furthermore, rather than BACE2 G446R , BACE2 WT 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. |
| first_indexed | 2024-04-11T17:53:13Z |
| format | Article |
| id | doaj.art-63accbef13334404804b8db41f612a6a |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-11T17:53:13Z |
| publishDate | 2022-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-63accbef13334404804b8db41f612a6a2022-12-22T04:11:00ZengNature Publishing GroupCell Death Discovery2058-77162022-02-01811810.1038/s41420-022-00845-5BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoidsJuan Luo0Hailin Zou1Yibo Guo2Ke Huang3Elly Sau-Wai Ngan4Peng Li5Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen UniversityDepartment of Surgery, Li Ka Shing Faculty of Medicine, University of Hong KongScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen UniversityAbstract 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 (BACE2 G446R ) 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 BACE2 G446R BOs. Furthermore, rather than BACE2 G446R , BACE2 WT 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.https://doi.org/10.1038/s41420-022-00845-5 |
| spellingShingle | Juan Luo Hailin Zou Yibo Guo Ke Huang Elly Sau-Wai Ngan Peng Li BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids Cell Death Discovery |
| title | BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids |
| title_full | BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids |
| title_fullStr | BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids |
| title_full_unstemmed | BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids |
| title_short | BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids |
| title_sort | bace2 variant identified from hscr patient causes ad like phenotypes in hpsc derived brain organoids |
| url | https://doi.org/10.1038/s41420-022-00845-5 |
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