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Enhancing autophagy maturation with CCZ1-MON1A complex alleviates neuropathology and memory defects in Alzheimer disease models
Cai, Cui Zan1,2; Zhuang, Xu Xu1; Zhu, Qi1; Wu, Ming Yue1; Su, Huanxing1; Wang, Xiao Jin2; Iyaswamy, Ashok3; Yue, Zhenyu4; Wang, Qian4,5,6; Zhang, Bin5,6,7,8; Xue, Yu9; Tan, Jieqiong10; Li, Min3; He, Huanhuan2; Lu, Jia Hong1
2022
Source PublicationTheranostics
Volume12Issue:4Pages:1738-1755
Abstract

Rationale: Impairment of autophagy maturation has been implicated in Alzheimer's disease (AD) pathogenesis. However, the mechanism for this impairment has not been elucidated, and whether enhancing autophagy maturation is a viable therapeutic strategy for AD has not been verified. Methods: We examined the autophagosome maturation process in AD cell and mouse models by immunoblotting. To further understand the changes in autophagy in AD brains, we analyzed the transcriptome by RNA-sequencing and measured the expression of RAB7, CCZ1 and MON1A. We performed brain stereotaxic injections of AAV into 3xTg AD mouse brain and WT mouse brain to over-express MON1A/CCZ1 or knockdown MON1A. For in vitro studies, we purified autophagosomes, and determined GTP-RAB7 level in autophagosome fractions by GST-R7BD affinity-isolation assay. Results: We report that the active form of RAB7 was selectively decreased in autophagosome fractions isolated from cells and tissues of AD models, and that this decrease was accompanied by impaired activity of its guanine nucleotide exchange factor (GFE) CCZ1-MON1A. Overexpressing CCZ1-MON1A increased the active form of RAB7, enhanced autophagosome maturation, and promoted degradation of APP-CTFs, Aβ and P-tau in an autophagy-dependent manner in cells and a mouse AD model. Conclusions: Our data reveals that CCZ1-MON1A-RAB7 complex dysfunction is a potential mechanism for autophagosome maturation defects in AD, and advances the possibility that enhancing autophagosome maturation is a novel therapeutic strategy against AD.

KeywordAlzheimer's Disease Autophagy Ccz1-mon1a Rab7
DOI10.7150/thno.64148
URLView the original
Language英語English
Scopus ID2-s2.0-85124197590
Fulltext Access
Citation statistics
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao
2.Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, China
3.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
4.Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, United States
5.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, 10029, United States
6.Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, 10029, United States
7.Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, 10029, United States
8.Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, United States
9.Key Laboratory of Molecular Biophysics of Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
10.Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, China
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Cai, Cui Zan,Zhuang, Xu Xu,Zhu, Qi,et al. Enhancing autophagy maturation with CCZ1-MON1A complex alleviates neuropathology and memory defects in Alzheimer disease models[J]. Theranostics,2022,12(4):1738-1755.
APA Cai, Cui Zan,Zhuang, Xu Xu,Zhu, Qi,Wu, Ming Yue,Su, Huanxing,Wang, Xiao Jin,Iyaswamy, Ashok,Yue, Zhenyu,Wang, Qian,Zhang, Bin,Xue, Yu,Tan, Jieqiong,Li, Min,He, Huanhuan,&Lu, Jia Hong.(2022).Enhancing autophagy maturation with CCZ1-MON1A complex alleviates neuropathology and memory defects in Alzheimer disease models.Theranostics,12(4),1738-1755.
MLA Cai, Cui Zan,et al."Enhancing autophagy maturation with CCZ1-MON1A complex alleviates neuropathology and memory defects in Alzheimer disease models".Theranostics 12.4(2022):1738-1755.
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