Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in mice
Abstract Background Dysfunctional autophagy is implicated in Alzheimer’s Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the disparity of the changes confounds the role of autophagy in AD. Methods To furthe...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-11-01
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| Series: | Molecular Neurodegeneration |
| Online Access: | http://link.springer.com/article/10.1186/s13024-019-0342-4 |
| _version_ | 1818858772256260096 |
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| author | Véronik Lachance Qian Wang Eric Sweet Insup Choi Cui-Zan Cai Xu-Xu Zhuang Yuanxi Zhang Jessica Li Jiang Robert D. Blitzer Ozlem Bozdagi-Gunal Bin Zhang Jia-Hong Lu Zhenyu Yue |
| author_facet | Véronik Lachance Qian Wang Eric Sweet Insup Choi Cui-Zan Cai Xu-Xu Zhuang Yuanxi Zhang Jessica Li Jiang Robert D. Blitzer Ozlem Bozdagi-Gunal Bin Zhang Jia-Hong Lu Zhenyu Yue |
| author_sort | Véronik Lachance |
| collection | DOAJ |
| description | Abstract Background Dysfunctional autophagy is implicated in Alzheimer’s Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the disparity of the changes confounds the role of autophagy in AD. Methods To further understand the autophagy alteration in AD brains, we analyzed transcriptomic (RNAseq) datasets of several brain regions (BA10, BA22, BA36 and BA44 in 223 patients compared to 59 healthy controls) and measured the expression of 130 ATGs. We used autophagy-deficient mouse models to assess the impact of the identified ATGs depletion on memory, autophagic activity and amyloid-β (Aβ) production. Results We observed significant downregulation of multiple components of two autophagy kinase complexes BECN1-PIK3C3 and ULK1/2-FIP200 specifically in the parahippocampal gyrus (BA36). Most importantly, we demonstrated that deletion of NRBF2, a component of the BECN1-PIK3C3 complex, which also associates with ULK1/2-FIP200 complex, impairs memory in mice, alters long-term potentiation (LTP), reduces autophagy in mouse hippocampus, and promotes Aβ accumulation. Furthermore, AAV-mediated NRBF2 overexpression in the hippocampus not only rescues the impaired autophagy and memory deficits in NRBF2-depleted mice, but also reduces β-amyloid levels and improves memory in an AD mouse model. Conclusions Our data not only implicates NRBF2 deficiency as a risk factor for cognitive impairment associated with AD, but also support the idea of NRBF2 as a potential therapeutic target for AD. |
| first_indexed | 2024-12-19T09:01:36Z |
| format | Article |
| id | doaj.art-08130cf12c0d4ff3966594d207ddd573 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-19T09:01:36Z |
| publishDate | 2019-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-08130cf12c0d4ff3966594d207ddd5732022-12-21T20:28:28ZengBMCMolecular Neurodegeneration1750-13262019-11-0114111310.1186/s13024-019-0342-4Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in miceVéronik Lachance0Qian Wang1Eric Sweet2Insup Choi3Cui-Zan Cai4Xu-Xu Zhuang5Yuanxi Zhang6Jessica Li Jiang7Robert D. Blitzer8Ozlem Bozdagi-Gunal9Bin Zhang10Jia-Hong Lu11Zhenyu Yue12Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount SinaiState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauDepartment of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartments of Psychiatry and Pharmacological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Neuroscience, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauDepartment of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount SinaiAbstract Background Dysfunctional autophagy is implicated in Alzheimer’s Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the disparity of the changes confounds the role of autophagy in AD. Methods To further understand the autophagy alteration in AD brains, we analyzed transcriptomic (RNAseq) datasets of several brain regions (BA10, BA22, BA36 and BA44 in 223 patients compared to 59 healthy controls) and measured the expression of 130 ATGs. We used autophagy-deficient mouse models to assess the impact of the identified ATGs depletion on memory, autophagic activity and amyloid-β (Aβ) production. Results We observed significant downregulation of multiple components of two autophagy kinase complexes BECN1-PIK3C3 and ULK1/2-FIP200 specifically in the parahippocampal gyrus (BA36). Most importantly, we demonstrated that deletion of NRBF2, a component of the BECN1-PIK3C3 complex, which also associates with ULK1/2-FIP200 complex, impairs memory in mice, alters long-term potentiation (LTP), reduces autophagy in mouse hippocampus, and promotes Aβ accumulation. Furthermore, AAV-mediated NRBF2 overexpression in the hippocampus not only rescues the impaired autophagy and memory deficits in NRBF2-depleted mice, but also reduces β-amyloid levels and improves memory in an AD mouse model. Conclusions Our data not only implicates NRBF2 deficiency as a risk factor for cognitive impairment associated with AD, but also support the idea of NRBF2 as a potential therapeutic target for AD.http://link.springer.com/article/10.1186/s13024-019-0342-4 |
| spellingShingle | Véronik Lachance Qian Wang Eric Sweet Insup Choi Cui-Zan Cai Xu-Xu Zhuang Yuanxi Zhang Jessica Li Jiang Robert D. Blitzer Ozlem Bozdagi-Gunal Bin Zhang Jia-Hong Lu Zhenyu Yue Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in mice Molecular Neurodegeneration |
| title | Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in mice |
| title_full | Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in mice |
| title_fullStr | Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in mice |
| title_full_unstemmed | Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in mice |
| title_short | Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in mice |
| title_sort | autophagy protein nrbf2 has reduced expression in alzheimer s brains and modulates memory and amyloid beta homeostasis in mice |
| url | http://link.springer.com/article/10.1186/s13024-019-0342-4 |
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