Linking the low‐density lipoprotein receptor‐binding segment enables the therapeutic 5‐YHEDA peptide to cross the blood‐brain barrier and scavenge excess iron and radicals in the brain of senescent mice
Abstract Introduction Iron accumulates in the brain during aging, which catalyzes radical formation, causing neuronal impairment, and is thus considered a pathogenic factor in Alzheimer's disease (AD). To scavenge excess iron‐catalyzed radicals and thereby protect the brain and decrease the inc...
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2019-01-01
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| Series: | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
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| Online Access: | https://doi.org/10.1016/j.trci.2019.07.013 |
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| author | Zhenyou Zou Shengxi Shao Ruyi Zou Jini Qi Liguan Chen Hui Zhang Qiqiong Shen Yue Yang Liman Ma Ruzeng Guo Hongwen Li Haibo Tian Pengxin Li Mingfang Yu Lu Wang Wenjuan Kong Caiyu Li Zhenhai Yu Yuping Huang Li Chen Qi Shao Xinyan Gao Xiaolin Chen Zhengbo Zhang Jianguo Yan Xiaoyun Shao Ru Pan Lu Xu Jing Fang Lei Zhao Yaohui Huang Anqi Li Yuchong Zhang Wenkao Huang Kechun Tian Minxin Hu Linchao Xie Lingbin Wu Yu Wu Zhen Luo Wenxin Xiao Shanshan Ma Jianan Wang Kaixin Huang Siyuan He Fan Yang Shuni Zhou Mo Jia Hui Zhang Hongsheng Lu Xinjuan Wang Jie Tan |
| author_facet | Zhenyou Zou Shengxi Shao Ruyi Zou Jini Qi Liguan Chen Hui Zhang Qiqiong Shen Yue Yang Liman Ma Ruzeng Guo Hongwen Li Haibo Tian Pengxin Li Mingfang Yu Lu Wang Wenjuan Kong Caiyu Li Zhenhai Yu Yuping Huang Li Chen Qi Shao Xinyan Gao Xiaolin Chen Zhengbo Zhang Jianguo Yan Xiaoyun Shao Ru Pan Lu Xu Jing Fang Lei Zhao Yaohui Huang Anqi Li Yuchong Zhang Wenkao Huang Kechun Tian Minxin Hu Linchao Xie Lingbin Wu Yu Wu Zhen Luo Wenxin Xiao Shanshan Ma Jianan Wang Kaixin Huang Siyuan He Fan Yang Shuni Zhou Mo Jia Hui Zhang Hongsheng Lu Xinjuan Wang Jie Tan |
| author_sort | Zhenyou Zou |
| collection | DOAJ |
| description | Abstract Introduction Iron accumulates in the brain during aging, which catalyzes radical formation, causing neuronal impairment, and is thus considered a pathogenic factor in Alzheimer's disease (AD). To scavenge excess iron‐catalyzed radicals and thereby protect the brain and decrease the incidence of AD, we synthesized a soluble pro‐iron 5‐YHEDA peptide. However, the blood‐brain barrier (BBB) blocks large drug molecules from entering the brain and thus strongly reduces their therapeutic effects. However, alternative receptor‐ or transporter‐mediated approaches are possible. Methods A low‐density lipoprotein receptor (LDLR)‐binding segment of Apolipoprotein B‐100 was linked to the 5‐YHEDA peptide (bs‐5‐YHEDA) and intracardially injected into senescent (SN) mice that displayed symptoms of cognitive impairment similar to those of people with AD. Results We successfully delivered 5‐YHEDA across the BBB into the brains of the SN mice via vascular epithelium LDLR‐mediated endocytosis. The data showed that excess brain iron and radical‐induced neuronal necrosis were reduced after the bs‐5‐YHEDA treatment, together with cognitive amelioration in the SN mouse, and that the senescence‐associated ferritin and transferrin increase, anemia and inflammation reversed without kidney or liver injury. Discussion bs‐5‐YHEDA may be a mild and safe iron remover that can cross the BBB and enter the brain to relieve excessive iron‐ and radical‐induced cognitive disorders. |
| format | Article |
| id | doaj-art-0efe6b958a2146158d5c29b0c1d39ec9 |
| institution | DOAJ |
| issn | 2352-8737 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
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| series | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| spelling | doaj-art-0efe6b958a2146158d5c29b0c1d39ec92025-08-20T03:22:00ZengWileyAlzheimer’s & Dementia: Translational Research & Clinical Interventions2352-87372019-01-015171773110.1016/j.trci.2019.07.013Linking the low‐density lipoprotein receptor‐binding segment enables the therapeutic 5‐YHEDA peptide to cross the blood‐brain barrier and scavenge excess iron and radicals in the brain of senescent miceZhenyou Zou0Shengxi Shao1Ruyi Zou2Jini Qi3Liguan Chen4Hui Zhang5Qiqiong Shen6Yue Yang7Liman Ma8Ruzeng Guo9Hongwen Li10Haibo Tian11Pengxin Li12Mingfang Yu13Lu Wang14Wenjuan Kong15Caiyu Li16Zhenhai Yu17Yuping Huang18Li Chen19Qi Shao20Xinyan Gao21Xiaolin Chen22Zhengbo Zhang23Jianguo Yan24Xiaoyun Shao25Ru Pan26Lu Xu27Jing Fang28Lei Zhao29Yaohui Huang30Anqi Li31Yuchong Zhang32Wenkao Huang33Kechun Tian34Minxin Hu35Linchao Xie36Lingbin Wu37Yu Wu38Zhen Luo39Wenxin Xiao40Shanshan Ma41Jianan Wang42Kaixin Huang43Siyuan He44Fan Yang45Shuni Zhou46Mo Jia47Hui Zhang48Hongsheng Lu49Xinjuan Wang50Jie Tan51Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaDivision of Cell and Molecular BiologyImperial College LondonLondonUnited KingdomChemistry Engineering DepartmentShangrao Normal UniversityShangraoJXChinaMedical School of Taizhou UniversityTaizhouZJChinaZhejiang Armed Police CorpsHangzhouZJChinaChina Tobacco Gene Research Center, Zhengzhou Tobacco Research Institute of CNTCZhengzhouHNChinaMedical School of Taizhou UniversityTaizhouZJChinaClinical Laboratory DepartmentWenzhou Medical UniversityZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaClinical Laboratory of Jingyou HospitalXiaoshanZJChinaMedical School of Taizhou UniversityTaizhouZJChinaChemistry Engineering DepartmentShangrao Normal UniversityShangraoJXChinaChemistry Engineering DepartmentShangrao Normal UniversityShangraoJXChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaChemistry Engineering DepartmentShangrao Normal UniversityShangraoJXChinaChemistry Engineering DepartmentShangrao Normal UniversityShangraoJXChinaChemistry Engineering DepartmentShangrao Normal UniversityShangraoJXChinaChemistry Engineering DepartmentShangrao Normal UniversityShangraoJXChinaChemistry Engineering DepartmentShangrao Normal UniversityShangraoJXChinaMedical School of Taizhou UniversityTaizhouZJChinaMedical School of Taizhou UniversityTaizhouZJChinaPathology DepartmentAffiliated Hospital of Taizhou UniversityZJChinaPathology DepartmentAffiliated Hospital of Taizhou UniversityZJChinaMedical School of Taizhou UniversityTaizhouZJChinaGuangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilinGXChinaAbstract Introduction Iron accumulates in the brain during aging, which catalyzes radical formation, causing neuronal impairment, and is thus considered a pathogenic factor in Alzheimer's disease (AD). To scavenge excess iron‐catalyzed radicals and thereby protect the brain and decrease the incidence of AD, we synthesized a soluble pro‐iron 5‐YHEDA peptide. However, the blood‐brain barrier (BBB) blocks large drug molecules from entering the brain and thus strongly reduces their therapeutic effects. However, alternative receptor‐ or transporter‐mediated approaches are possible. Methods A low‐density lipoprotein receptor (LDLR)‐binding segment of Apolipoprotein B‐100 was linked to the 5‐YHEDA peptide (bs‐5‐YHEDA) and intracardially injected into senescent (SN) mice that displayed symptoms of cognitive impairment similar to those of people with AD. Results We successfully delivered 5‐YHEDA across the BBB into the brains of the SN mice via vascular epithelium LDLR‐mediated endocytosis. The data showed that excess brain iron and radical‐induced neuronal necrosis were reduced after the bs‐5‐YHEDA treatment, together with cognitive amelioration in the SN mouse, and that the senescence‐associated ferritin and transferrin increase, anemia and inflammation reversed without kidney or liver injury. Discussion bs‐5‐YHEDA may be a mild and safe iron remover that can cross the BBB and enter the brain to relieve excessive iron‐ and radical‐induced cognitive disorders.https://doi.org/10.1016/j.trci.2019.07.013Alzheimer's diseaseSenescent mousebs‐5‐YHEDABlood‐brain barrierLDLRApoB‐100 |
| spellingShingle | Zhenyou Zou Shengxi Shao Ruyi Zou Jini Qi Liguan Chen Hui Zhang Qiqiong Shen Yue Yang Liman Ma Ruzeng Guo Hongwen Li Haibo Tian Pengxin Li Mingfang Yu Lu Wang Wenjuan Kong Caiyu Li Zhenhai Yu Yuping Huang Li Chen Qi Shao Xinyan Gao Xiaolin Chen Zhengbo Zhang Jianguo Yan Xiaoyun Shao Ru Pan Lu Xu Jing Fang Lei Zhao Yaohui Huang Anqi Li Yuchong Zhang Wenkao Huang Kechun Tian Minxin Hu Linchao Xie Lingbin Wu Yu Wu Zhen Luo Wenxin Xiao Shanshan Ma Jianan Wang Kaixin Huang Siyuan He Fan Yang Shuni Zhou Mo Jia Hui Zhang Hongsheng Lu Xinjuan Wang Jie Tan Linking the low‐density lipoprotein receptor‐binding segment enables the therapeutic 5‐YHEDA peptide to cross the blood‐brain barrier and scavenge excess iron and radicals in the brain of senescent mice Alzheimer’s & Dementia: Translational Research & Clinical Interventions Alzheimer's disease Senescent mouse bs‐5‐YHEDA Blood‐brain barrier LDLR ApoB‐100 |
| title | Linking the low‐density lipoprotein receptor‐binding segment enables the therapeutic 5‐YHEDA peptide to cross the blood‐brain barrier and scavenge excess iron and radicals in the brain of senescent mice |
| title_full | Linking the low‐density lipoprotein receptor‐binding segment enables the therapeutic 5‐YHEDA peptide to cross the blood‐brain barrier and scavenge excess iron and radicals in the brain of senescent mice |
| title_fullStr | Linking the low‐density lipoprotein receptor‐binding segment enables the therapeutic 5‐YHEDA peptide to cross the blood‐brain barrier and scavenge excess iron and radicals in the brain of senescent mice |
| title_full_unstemmed | Linking the low‐density lipoprotein receptor‐binding segment enables the therapeutic 5‐YHEDA peptide to cross the blood‐brain barrier and scavenge excess iron and radicals in the brain of senescent mice |
| title_short | Linking the low‐density lipoprotein receptor‐binding segment enables the therapeutic 5‐YHEDA peptide to cross the blood‐brain barrier and scavenge excess iron and radicals in the brain of senescent mice |
| title_sort | linking the low density lipoprotein receptor binding segment enables the therapeutic 5 yheda peptide to cross the blood brain barrier and scavenge excess iron and radicals in the brain of senescent mice |
| topic | Alzheimer's disease Senescent mouse bs‐5‐YHEDA Blood‐brain barrier LDLR ApoB‐100 |
| url | https://doi.org/10.1016/j.trci.2019.07.013 |
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