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Enhancing autophagy maturation with CCZ1-MON1A complex alleviates neuropathology and memory defects in Alzheimer disease models.

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机构： [1]State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China [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 SAR, China [4]Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA [5]Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA [6]Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA [7]Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA [8]Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA [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

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关键词： Alzheimer’s disease Aβ Autophagy CCZ1-MON1A RAB7

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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.© The author(s).

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出版当年[2021]版：

大类 | 1 区

医学

小类 | 1 区医学：研究与实验

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大类 | 1 区

医学

小类 | 1 区医学：研究与实验

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第一作者机构： [1]State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China [2]Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, China

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Enhancing autophagy maturation with CCZ1-MON1A complex alleviates neuropathology and memory defects in Alzheimer disease models.

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