The autocrine motility factor receptor delays the pathological progression of Alzheimer’s disease via regulating the ubiquitination-mediated degradation of APP
Abstract Background The ubiquitin-proteasome system (UPS) is responsible for most protein degradation and its malfunction is normally observed in neurodegenerative diseases, including Alzheimer’s disease (AD). The autocrine motility factor receptor (AMFR) is an E3 ubiquitin ligase that resides on th...
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BMC
2025-04-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-025-01741-7 |
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| author | Jingjing Zhang Congcong Liu Jing Liu Yuting Cui Yuli Hou Qiao Song Xiaomin Zhang Xiaoling Wang Qian Zhang Min Cao Wenchao Wang Peichang Wang Yaqi Wang |
| author_facet | Jingjing Zhang Congcong Liu Jing Liu Yuting Cui Yuli Hou Qiao Song Xiaomin Zhang Xiaoling Wang Qian Zhang Min Cao Wenchao Wang Peichang Wang Yaqi Wang |
| author_sort | Jingjing Zhang |
| collection | DOAJ |
| description | Abstract Background The ubiquitin-proteasome system (UPS) is responsible for most protein degradation and its malfunction is normally observed in neurodegenerative diseases, including Alzheimer’s disease (AD). The autocrine motility factor receptor (AMFR) is an E3 ubiquitin ligase that resides on the endoplasmic reticulum membrane and is involved in various essential biological processes. However, the role of AMFR in AD is still unidentified. Methods Behavioral experiments, including open-field test (OFT), novel object recognition test (NORT) and morris water maze test (MWMT) were conducted after adeno-associated virus (AAV) microinjection into AD model mice. Western blot, co-immunoprecipitation (Co-IP), qPCR and ubiquitination assay were used to analyze AMFR mediated ubiquitination degradation of amyloid precursor protein (APP). ELISA was employed to evaluate changes in amyloidogenic cleavage products of APP following upregulation or downregulation of AMFR in neural cells and analyze AMFR levels in serum and cerebrospinal fluid (CSF) of AD patients. Results The progressive decline in AMFR levels was found not only in the hippocampus of APPswe/PSEN1dE9 (APP/PS1) mice but also in the CSF and serum of patients with AD. Moreover, the interaction of AMFR and APP was observed both in hippocampal tissues and brain neurons. In addition, AMFR promoted the K11-linked polyubiquitination of APP to speed up its proteasomal degradation, resulting in decreased Aβ production. Importantly, AMFR overexpression largely rescued the cognitive and synaptic deficits in APP/PS1 mice. Conclusions Taken together, our results demonstrated that AMFR reduced Aβ production and alleviated cognitive impairment by promoting the ubiquitination-mediated degradation of APP. This study indicated that AMFR could have the potential to be a therapeutic target of early-stage AD. |
| format | Article |
| id | doaj-art-786ec67bec3e41bbbc735d7d3086e1e7 |
| institution | DOAJ |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-786ec67bec3e41bbbc735d7d3086e1e72025-08-20T02:55:31ZengBMCAlzheimer’s Research & Therapy1758-91932025-04-0117112010.1186/s13195-025-01741-7The autocrine motility factor receptor delays the pathological progression of Alzheimer’s disease via regulating the ubiquitination-mediated degradation of APPJingjing Zhang0Congcong Liu1Jing Liu2Yuting Cui3Yuli Hou4Qiao Song5Xiaomin Zhang6Xiaoling Wang7Qian Zhang8Min Cao9Wenchao Wang10Peichang Wang11Yaqi Wang12Department and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment of Clinical Laboratory, Beijing Huairou HospitalDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityDepartment and Institute of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical UniversityAbstract Background The ubiquitin-proteasome system (UPS) is responsible for most protein degradation and its malfunction is normally observed in neurodegenerative diseases, including Alzheimer’s disease (AD). The autocrine motility factor receptor (AMFR) is an E3 ubiquitin ligase that resides on the endoplasmic reticulum membrane and is involved in various essential biological processes. However, the role of AMFR in AD is still unidentified. Methods Behavioral experiments, including open-field test (OFT), novel object recognition test (NORT) and morris water maze test (MWMT) were conducted after adeno-associated virus (AAV) microinjection into AD model mice. Western blot, co-immunoprecipitation (Co-IP), qPCR and ubiquitination assay were used to analyze AMFR mediated ubiquitination degradation of amyloid precursor protein (APP). ELISA was employed to evaluate changes in amyloidogenic cleavage products of APP following upregulation or downregulation of AMFR in neural cells and analyze AMFR levels in serum and cerebrospinal fluid (CSF) of AD patients. Results The progressive decline in AMFR levels was found not only in the hippocampus of APPswe/PSEN1dE9 (APP/PS1) mice but also in the CSF and serum of patients with AD. Moreover, the interaction of AMFR and APP was observed both in hippocampal tissues and brain neurons. In addition, AMFR promoted the K11-linked polyubiquitination of APP to speed up its proteasomal degradation, resulting in decreased Aβ production. Importantly, AMFR overexpression largely rescued the cognitive and synaptic deficits in APP/PS1 mice. Conclusions Taken together, our results demonstrated that AMFR reduced Aβ production and alleviated cognitive impairment by promoting the ubiquitination-mediated degradation of APP. This study indicated that AMFR could have the potential to be a therapeutic target of early-stage AD.https://doi.org/10.1186/s13195-025-01741-7Alzheimer’s diseaseAutocrine motility factor receptorUbiquitinationE3 ubiquitin ligaseAmyloid precursor protein |
| spellingShingle | Jingjing Zhang Congcong Liu Jing Liu Yuting Cui Yuli Hou Qiao Song Xiaomin Zhang Xiaoling Wang Qian Zhang Min Cao Wenchao Wang Peichang Wang Yaqi Wang The autocrine motility factor receptor delays the pathological progression of Alzheimer’s disease via regulating the ubiquitination-mediated degradation of APP Alzheimer’s Research & Therapy Alzheimer’s disease Autocrine motility factor receptor Ubiquitination E3 ubiquitin ligase Amyloid precursor protein |
| title | The autocrine motility factor receptor delays the pathological progression of Alzheimer’s disease via regulating the ubiquitination-mediated degradation of APP |
| title_full | The autocrine motility factor receptor delays the pathological progression of Alzheimer’s disease via regulating the ubiquitination-mediated degradation of APP |
| title_fullStr | The autocrine motility factor receptor delays the pathological progression of Alzheimer’s disease via regulating the ubiquitination-mediated degradation of APP |
| title_full_unstemmed | The autocrine motility factor receptor delays the pathological progression of Alzheimer’s disease via regulating the ubiquitination-mediated degradation of APP |
| title_short | The autocrine motility factor receptor delays the pathological progression of Alzheimer’s disease via regulating the ubiquitination-mediated degradation of APP |
| title_sort | autocrine motility factor receptor delays the pathological progression of alzheimer s disease via regulating the ubiquitination mediated degradation of app |
| topic | Alzheimer’s disease Autocrine motility factor receptor Ubiquitination E3 ubiquitin ligase Amyloid precursor protein |
| url | https://doi.org/10.1186/s13195-025-01741-7 |
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