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Enhanced autophagic clearance of amyloid-βvia histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

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Neural Regeneration Research 2025年第9期20卷 2633-2644页

作者： Zhimin Long Chuanhua Ge Yueyang Zhao Yuanjie Liu Qinghua Zeng Qing Tang Zhifang Dong guiqiong he Institute of Neuroscience School of Basic Medical SciencesChongqing Medical UniversityChongqingChina Department of Anatomy Chongqing Medical UniversityChongqingChina Department of Physiology Chongqing Medical UniversityChongqingChina Pediatric Research Institute Children’s Hospital of Chongqing Medical UniversityChongqingChina Ministry of Education Key Laboratory of Child Development and Disorders Children’s Hospital of Chongqing Medical UniversityChongqingChina National Clinical Research Center for Child health and Disorders Children’s Hospital of Chongqing Medical UniversityChongqingChina Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders Children’s Hospital of Chongqing Medical UniversityChongqingChina

Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque ***,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's *** acetylation/deacetylation plays a central role in lysosomal ***,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's *** rthermore,we found that treatment with valproic acid markedly enhanced *** clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's *** findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.

关键词： Alzheimer's disease amyloid-β APP/PS1 mice autophagy cognitive impairment histone deacetylase 6 lysosomal acidification microtubule acetylation valproic acid V-ATPase

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Structure,function,and pathology of Neurexin-3

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Genes & Diseases 2023年第5期10卷 1908-1919页

作者： Rui Zhang HanXiao Jiang YuanJie Liu guiqiong he Chongqing Key Laboratory of Neurobiology Chongqing Medical UniversityChongqing 400016China Department of Neurology The Second Affiliated HospitalChongqing Medical UniversityChongqing 400010China Department of Anatomy Chongqing Medical UniversityChongqing 400016China

Neurexin-3 is primarily localized in the presynaptic membrane and forms complexes with various ligands located in the postsynaptic ***-3 has important roles in synapse development and synapse ***-3 mediates excitatory presynaptic differentiation by interacting with leucine-rich-repeat transmembrane neuronal ***,neurexin-3 modulates the expression of presynapticα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors andγ-aminobutyric acid A receptors by interacting with neuroligins at excitatory and inhibitory *** studies have documented the potential contribution of neurexin-3 to neurodegenerative and neuropsychiatric disorders,such as Alzheimer's disease,addiction behaviors,and other diseases,which raises hopes that understanding the mechanisms of neurexin-3 may hold the key to developing new strategies for related *** review comprehensively covers the literature to provide current knowledge of the structure,function,and clinical role of neurexin-3.

关键词： Excitatory synapses Inhibitory synapses Neural cell adhesion molecules Neurexin-3 Neurodegenerative diseases Neuropsychiatric diseases

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Alterations in expression and localization of POMGNT1 in the APP/PS1 mouse model of Alzheimer’s disease

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Genes & Diseases 2024年第5期11卷 55-58页

作者： Hanxiao Jiang Yuxue Feng Xia Hao guiqiong he Xiaofeng Li Department of Neurology The Second Affiliated Hospital of Chongqing Medical UniversityChongqing 401336China Chongqing Key Laboratory of Neurobiology Chongqing Medical UniversityChongqing 400016China Department of Anatomy Chongqing Medical UniversityChongqing 400016China Department of Neurology The Fifth People’s Hospital of ChongqingChongqing 400062China

Alzheimer’s disease(AD)is a complex and progressive neurodegenerative disorder that causes dementia in the aging *** of the characteristic pathologic hallmarks of AD is the senile plaques,composed of the accumulation of *** b-amyloid results from the cleavage of transmembrane b-amyloid precursor protein(APP)by b-secretases and g-secretases,sequentially.O-mannosylation was found essential for the normal function of APP in Saccharomyces cerevisiae.1 Protein Olinked mannose b1,2-N-acetyl-glucosaminyltransferase 1(POMGNT1)is a glycosyltransferase crucial for the elongation of O-mannosyl glycans and catalyzes the transfer of Nacetylglucosamine from uridine 50-diphosphate-N-acetylglucosamine to O-mannose of glycoproteins.

关键词： APP/PS1 Alzheimer amyloid

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Liquiritigenin promotes osteogenic differentiation and prevents bone loss via inducing auto-lysosomal degradation and inhibiting apoptosis

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Genes & Diseases 2023年第1期10卷 284-300页

作者： Yu Qiu Yueyang Zhao Zhimin Long Aijia Song Peng Huang Kejian Wang Ling Xu David Paul Molloy guiqiong he College of Stomatology Chongqing Medical UniversityChongqing Key Laboratory of Oral Diseases and Biomedical SciencesChongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing400016China Chongqing Key Laboratory of Neurobiology Chongqing Medical UniversityChongqing 400016China Department of Anatomy Chongqing Medical UniversityChongqing 400016China Laboratory of Medical Experiment Technology Institute of Life ScienceChongqing Medical UniversityChongqing 400016China Department of Biochemistry and Molecular Biology Chongqing Medical UniversityChongqing 400016China

Osteoporosis(OP)is a debilitating skeletal abnormality involving bone remodeling and bone cell homeostasis characterized by decreased bone strength and high fracture risk.A novel therapeutic intervention for OP by manipulating cellular autophagy-apoptosis processes to promote skeletal homeostasis is *** effects of the naturally occurring plant extract Liquiritigenin(LG)were demonstrated in an ovariectomy(OvX)-OP mouse model and preosteoblast MC3T3-E1 ***-CT and histological staining assessments of skeletal phenotype were applied alongside detection of autophagy activity in osteocytes and MC3T3-E1 cells by transmission electron microscopy(TEM).The effects of LG on chloroquine(CQ)-and the apoptosis-inducing TS-treated osteogenic differentiations and status of lysosomes within MC3T3-E1 cells were analyzed by Neutral red,Alizarin red S and alkaline phosphatase(ALP)staining and Western blot *** with LG prevented bone loss,increased osteogenic differentiation in vivo and in vitro,and inhibited osteoclast formation to some *** analyses revealed that LG can improve auto-lysosomal degradation within osteocytes from OVX mice and MC3T3-E1 *** abnormal status of lysosomes associated with CQ and TS treatments was notably alleviated by LG which also reduced levels of apoptosis-induced inhibition of osteogenic differentiation and averted abnormal osteogenic differentiation as a consequence of a blockage in autolysosome ***,LG stimulates bone growth in Oovx mice through increased osteogenic differentiation and regulation of autophagyapoptosis mechanisms,presenting an auspicious natural therapy for Op.

关键词： Apoptosis Auto-lysosomal degradation Liquiritigenin Osteogenic differentiation Osteoporosis

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Estrogen deficiency exacerbates learning and memory deficits associated with glucose metabolism disorder in APP/PS1 double transgenic female mice

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Genes & Diseases 2022年第5期9卷 1315-1331页

作者： Min Luo Qinghua Zeng Kai Jiang Yueyang Zhao Zhimin Long Yexiang Du Kejian Wang guiqiong he Chongqing Key Laboratory of Neurobiology Chongqing Medical UniversityChongqing 400016PR China Department of Pathology Suining Municipal Hospital of TCMSuiningSichuan 629000PR China Department of Anatomy Chongqing Medical UniversityChongqing 400016PR China Department of Gastroenterology Suining Central HospitalSuiningSichuan 629000PR China

Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease(AD),and menopausal women have more severe metabolic dysfunction and are more prone to dementia than *** estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models,their molecular mechanisms in AD remain *** investigate this issue,double transgenic(APP/PS1)female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week,1 month and 3 months after surgery to simulate early,middle and late postmenopause,*** analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of *** deficiency impairs the function of mitochondria in glucose *** is possible that the occurrence of AD is associated with the aberrant mitochondrial ERβ-mediated IGF-1/IGF-1R/GSK-3βsignaling *** this study,we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause.

关键词： Alzheimer’s disease Estrogen deficiency Glucose metabolism disorder GSK-3b IGF-1 Mitochondria

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miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1- containing AMPA receptors in a mouse model of Alzheimer’s disease

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Acta Pharmaceutica Sinica B 2024年第2期14卷 635-652页

作者： Man Luo Yayan Pang Junjie Li Lilin Yi Bin Wu Qiuyun Tian Yan he Maoju Wang Lei Xia guiqiong he Weihong Song Yehong Du Zhifang Dong Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChina International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren’s Hospital of Chongqing Medical UniversityChongqing 400014China Department of Anatomy Basic Medical CollegeChongqing Medical UniversityChongqing 400016China Townsend Family Laboratories Department of PsychiatryThe University of British ColumbiaVancouver BC V6T 1Z3Canada Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Institute of AgingKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceZhejiang Clinical Research Center for Mental DisordersSchool of Mental Health and the Affiliated Kangning HospitalWenzhou Medical UniversityWenzhou 325000China Institute for Brain Science and Disease of Chongqing Medical University Chongqing 400016China

Alzheimer ’s disease(AD) is a leading cause of dementia in the ***-activated protein kinase phosphatase 1(MKP-1) plays a neuroprotective role in ***,the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively ***(miRNAs) regulate gene expression at the post-transcriptional level,thereby repressing mRNA ***,we reported that the microRNA-429-3p(miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPPAD model *** further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3’-untranslated region(3’ UTR).Inhibition of miR-429-3p by its antagomir(A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ *** importantly,intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase(ERK1/2)-mediated GluAl hyperphosphorylation at Ser831 site,thereby increasing the surface expression of GluAl-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors(AMPARs).Together,these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice,suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

关键词： Alzheimer's disease MKP-1 miR-429-3p AMPAreceptor Learning and memory Long-term potentiation

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Coexistence of dopamine-beta-hydroxylase and activated protein-2 alpha in rat cerebellar Purkinje cells

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Neural Regeneration Research 2009年第6期4卷 431-435页

作者： Kejian Wang Wei Li Shanquan Sun Zhongqin Ren guiqiong he Department of Human Anatomy Coflege of Basic Medicine Chongqing Medical University Chongqing 400016 China Institute of Neuroscience Chongqing Medical University Chongqing 400016 China

BACKGROUND： Tyrosine hydroxylase and phenylethanolamine-n-methyl transferase expression coexist in Purkinje cells of the rat cerebellum. Numerous reports have also been published addressing whether dopamine-beta-hydroxylase （DBH） expression exists in cerebellar Purkinje cells. OBJECTIVE： To investigate the coexistence of DBH and activator protein-2α expression in rat cerebellar Purkinje cells. DESIGN, TIME AND SETTING： A cell morphological study was performed at the Institute of Neuroscience, Chongqing Medical University, China in May 2007. MATERIALS： Ten healthy Wistar rats, of either gender, aged 14 weeks, served as experimental animals. Rabbit anti-mouse DBH, goat anti-mouse activator protein-2α and rabbit anti-mouse β-actin （Santa Cruz Biotechnology, Inc., USA）, horseradish peroxidase-labeled goat anti-rabbit IgG, FITC-labeled mouse anti-rabbit IgG, and Cy3-labeled mouse anti-goat IgG （Boster, Wuhan, China）, were used in this study. METHODS： Immunohistochemical staining was used to measure the expression of DBH or activator protein-2α, with double-label immunofluorescence being employed to determine coexpression of both, in the cerebellum of 5 randomly selected rats. Western blot assay was utilized to determine the expression of DBH and activator protein-2α in the cerebellum of the remaining 5 rats. MAIN OUTCOME MEASURES： Expression, localization and coexistence of DBH and activator protein-2α in the cerebellum were measured separately. RESULTS： Immunohistochemical staining demonstrated that cerebellar Purkinje cells stained positive for DBH and activator protein-2α. Western blot assay also demonstrated DBH and activator protein-2α expression in the cerebellum. Double-labeling immunofluorescence showed the coexistence of DBH and activator protein-2α in cerebellar Purkinje cells. CONCLUSION： Norepinephrine and activator protein-2α coexist in rat cerebellar Purkinje cells.

关键词： Purkinje cells cerebellum dopamine-beta-hydroxylase activator protein-2α

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Aquaporin-4 in the formation of cerebral edema following severe burns What role do arginine vasopressin levels play?

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Neural Regeneration Research 2010年第7期5卷 531-537页

作者： Shifang Luo Shanquan Sun Jianhua Ran Kejian Wang guiqiong he Department of Anatomy Chongqing Medical University Chongqing 400016 China Research Center of Neuroscience Chongqing Medical University Chongqing 400016 China

BACKGROUND： Aquaporin-4 （AQP-4）, which is able to rapidly transport water within the brain, is highly expressed in brain tissue. It also plays an important role in the formation of cerebral edema following brain injury. However, the role of AQP-4 in the formation of cerebral edema following severe bums remains unknown. OBJECTIVE： To study changes in AQP-4 protein and mRNA expression during formation of cerebral edema following severe burns, and to explore the correlation between AQP-4 protein and mRNA expression with plasma levels of arginine vasopressin （AVP）. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Research Center of Neuroscience, Chongqing Medical University from 2007 to 2008. MATERIALS： Biotin-labeled goat anti-rabbit antibody was provided by Beijing Zhongshan Biotechnology, China; in situ hybridization kit was provided by Wuhan Boster Biotechnology, China; rabbit anti-AQP-4 polyclonal antibody and horseradish peroxidase-labeled goat anti-rabbit IgG were provided by Chemicon, USA; AVP radioimmunoassay kit was provided by the Research Department of Neurobiology, the Second Military Medical University of Shanghai, China. METHODS： A total of 180 adult, healthy, Wistar rats were randomly assigned to control and burn groups with 30 rats in each group. The burn group was observed at five different time points： 2, 6, 12, 24, and 48 hours after burn. Hair on the mouse back was removed to expose skin on the back. After 1 day, skin with the hair removed was dipped into 100℃ water for 15 seconds to induce grade III bum injury that measures 30% of total bum surface area. MAIN OUTCOME MEASURES： Brain water content was measured using the dry-wet weight method. AQP-4 protein and mRNA expressions were detected using immunohistochemistry, in situ hybridization, Western blot, and reverse transcription-polymerase chain reaction; dynamic changes in plasma AVP were detected using radioimmunoassay. RESULTS： Brain water content gradua

关键词： burn injury cerebral edema aquaporin-4 aquaporin-4 mRNA arginine vasopressin brain injury

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MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models

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Signal Transduction and Targeted Therapy 2019年第1期4卷 149-160页

作者： Yehong Du Yexiang Du Yun Zhang Zhilin Huang Min Fu Junjie Li Yayan Pang Peng Lei Yu Tian Wang Weihong Song guiqiong he Zhifang Dong Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChina International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren’s Hospital of Chongqing Medical UniversityChongqing400014PR China Department of Anatomy Basic Medical CollegeChongqing Medical UniversityChongqing400016PR China Townsend Family Laboratories Department of PsychiatryThe University of British ColumbiaVancouverBCV6T 1Z3Canada West China School of Basic Medical Sciences and Forensic Medicine Sichuan UniversityChengdu610041SichuanChina Brain Research Centre The University of British ColumbiaVancouverBCV6T 2B5Canada

Mitogen-activated protein kinase(MAPK)phosphatase 1(MKP-1)is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine *** of the MAPK signaling pathway has been associated with Alzheimer’s disease(AD).However,the role of MKP-1 in AD pathogenesis remains ***,we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse *** reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1(Sp1)cis-acting binding elements in the MKP-1 gene ***-β(Aβ)-induced Sp1 activation decreased MKP-1 ***,upregulation of MKP-1 inhibited the expression of both Aβprecursor protein(APP)andβ-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2(ERK)/MAPK signaling ***,upregulation of MKP-1 reduced Aβproduction and plaque formation and improved hippocampal long-term potentiation(LTP)and cognitive deficits in APP/PS1 transgenic *** results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD,whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related ***,this study suggests that MKP-1 is a novel molecule for AD treatment.

关键词： Alzheimer Aβ impairment

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Hippocampal neurogenesis in APP/PS1/Nestin-GFP triple transgenic mouse model of Alzheimer’s disease

Hippocampal neurogenesis in APP/PS1/Nestin-GFP triple transg...

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中国解剖学会2015年年会

作者： Zeng Qinghua he guiqiong Institute of Neuroscience Chongqing Medical University

＜正＞Alzheimer’s disease（AD）is the most common cause of *** the exact mechanisms of AD are unknown,the impairments in adult hippocampal neurogenesis have been reported to play a role in *** assess the relationship between AD and neurogenesis,we studied APP/PS1/Nestin-GFP triple transgenic mice,a mouse model of AD that express green fluorescent protein under the control of the nestin ***

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