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Autophagy protein NRBF2 has reduced expression in Alzheimer's brains and modulates memory and amyloid-beta homeostasis in mice
Lachance,Véronik1; Wang,Qian1,2; Sweet,Eric1,3,4; Choi,Insup1; Cai,Cui Zan5; Zhuang,Xu Xu5; Zhang,Yuanxi1; Jiang,Jessica Li1; Blitzer,Robert D.3; Bozdagi-Gunal,Ozlem6,7; Zhang,Bin2; Lu,Jia Hong5; Yue,Zhenyu1
2019-11-27
Source PublicationMolecular Neurodegeneration
ISSN1750-1326
Volume14Issue:1
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.

DOI10.1186/s13024-019-0342-4
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaNeurosciences & Neurology
WOS SubjectNeurosciences
WOS IDWOS:000501018200001
Scopus ID2-s2.0-85075749704
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Cited Times [WOS]:12   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Corresponding AuthorLu,Jia Hong; Yue,Zhenyu
Affiliation1.Department of Neurology,Friedman Brain Institute,Icahn School of Medicine at Mount Sinai,New York,10029,United States
2.Department of Genetics and Genomic Sciences,Icahn School of Medicine at Mount Sinai,New York,10029,United States
3.Departments of Psychiatry and Pharmacological Sciences,Icahn School of Medicine at Mount Sinai,New York,10029,United States
4.Department of Biology,West Chester University,West Chester,19383,United States
5.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Taipa,Macao
6.Department of Neuroscience,Icahn School of Medicine at Mount Sinai,New York,10029,United States
7.Department of Psychiatry,Rutgers New Jersey Medical School,Newark,07103,United States
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Lachance,Véronik,Wang,Qian,Sweet,Eric,et al. Autophagy protein NRBF2 has reduced expression in Alzheimer's brains and modulates memory and amyloid-beta homeostasis in mice[J]. Molecular Neurodegeneration,2019,14(1).
APA Lachance,Véronik,Wang,Qian,Sweet,Eric,Choi,Insup,Cai,Cui Zan,Zhuang,Xu Xu,Zhang,Yuanxi,Jiang,Jessica Li,Blitzer,Robert D.,Bozdagi-Gunal,Ozlem,Zhang,Bin,Lu,Jia Hong,&Yue,Zhenyu.(2019).Autophagy protein NRBF2 has reduced expression in Alzheimer's brains and modulates memory and amyloid-beta homeostasis in mice.Molecular Neurodegeneration,14(1).
MLA Lachance,Véronik,et al."Autophagy protein NRBF2 has reduced expression in Alzheimer's brains and modulates memory and amyloid-beta homeostasis in mice".Molecular Neurodegeneration 14.1(2019).
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