TY - JOUR
T1 - Autophagy protein NRBF2 has reduced expression in Alzheimer's brains and modulates memory and amyloid-beta homeostasis in mice
AU - Lachance, Véronik
AU - Wang, Qian
AU - Sweet, Eric
AU - Choi, Insup
AU - Cai, Cui Zan
AU - Zhuang, Xu Xu
AU - Zhang, Yuanxi
AU - Jiang, Jessica Li
AU - Blitzer, Robert D.
AU - Bozdagi-Gunal, Ozlem
AU - Zhang, Bin
AU - Lu, Jia Hong
AU - Yue, Zhenyu
N1 - Funding Information:
This work was supported by NIH/NINDS R01-NS060123 (Z.Y.), NIH/NIMH R01- MH103455 (O.B-G.), 2U01AG046170–06 (B.Z.), YS2017YFGH000899, FDCT-024/ 2017/AMJ, FDCT-022/2015/A1 (J-H.L), and CIHR postdoctoral fellowship MFE- 146812 (V.L.).
Publisher Copyright:
© 2019 The Author(s).
PY - 2019/11/27
Y1 - 2019/11/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075749704&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075749704&partnerID=8YFLogxK
U2 - 10.1186/s13024-019-0342-4
DO - 10.1186/s13024-019-0342-4
M3 - Article
C2 - 31775806
AN - SCOPUS:85075749704
VL - 14
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
SN - 1750-1326
IS - 1
M1 - 43
ER -