Low‐Density Lipoprotein Receptor‐Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes
Abstract Early changes in astrocyte energy metabolism are associated with late‐onset Alzheimer's disease (LOAD), but the underlying mechanism remains elusive. A previous study suggested an association between a synonymous SNP (rs1012672, C→T) in LRP6 gene and LOAD; and that is indeed correlated...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-08-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202004993 |
| _version_ | 1818735377628790784 |
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| author | Hei‐Man Chow Jacquelyne Ka‐Li Sun Ronald P. Hart Kenneth King‐Yip Cheng Clara H. L. Hung Tsun‐Ming Lau Kin‐Ming Kwan |
| author_facet | Hei‐Man Chow Jacquelyne Ka‐Li Sun Ronald P. Hart Kenneth King‐Yip Cheng Clara H. L. Hung Tsun‐Ming Lau Kin‐Ming Kwan |
| author_sort | Hei‐Man Chow |
| collection | DOAJ |
| description | Abstract Early changes in astrocyte energy metabolism are associated with late‐onset Alzheimer's disease (LOAD), but the underlying mechanism remains elusive. A previous study suggested an association between a synonymous SNP (rs1012672, C→T) in LRP6 gene and LOAD; and that is indeed correlated with diminished LRP6 gene expression in the frontal cortex region. The authors show that LRP6 is a unique Wnt coreceptor on astrocytes, serving as a bimodal switch that modulates their metabolic landscapes. The Wnt‐LRP6 mediated mTOR‐AKT axis is essential for sustaining glucose metabolism. In its absence, Wnt switches to activate the LRP6‐independent Ca2+‐PKC‐NFAT axis, resulting in a transcription network that favors glutamine and branched chain amino acids (BCAAs) catabolism over glucose metabolism. Exhaustion of these raw materials essential for neurotransmitter biosynthesis and recycling results in compromised synaptic, cognitive, and memory functions; priming for early changes that are frequently found in LOAD. The authors also highlight that intranasal supplementation of glutamine and BCAAs is effective in preserving neuronal integrity and brain functions, proposing a nutrient‐based method for delaying cognitive and memory decline when LRP6 cell surface levels and functions are suboptimal. |
| first_indexed | 2024-12-18T00:20:17Z |
| format | Article |
| id | doaj.art-20179694e8944d0e88c9468969d8d620 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-18T00:20:17Z |
| publishDate | 2021-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-20179694e8944d0e88c9468969d8d6202022-12-21T21:27:20ZengWileyAdvanced Science2198-38442021-08-01816n/an/a10.1002/advs.202004993Low‐Density Lipoprotein Receptor‐Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in AstrocytesHei‐Man Chow0Jacquelyne Ka‐Li Sun1Ronald P. Hart2Kenneth King‐Yip Cheng3Clara H. L. Hung4Tsun‐Ming Lau5Kin‐Ming Kwan6School of Life Sciences, Faculty of Science The Chinese University of Hong Kong 999077 Hong KongSchool of Life Sciences, Faculty of Science The Chinese University of Hong Kong 999077 Hong KongDepartment of Cell Biology and Neuroscience Rutgers University Piscataway NJ 08854 USADepartment of Health Technology and Informatics The Hong Kong Polytechnic University 999077 Hong KongThe University Research Facility in Life Sciences The Hong Kong Polytechnic University 999077 Hong KongSchool of Life Sciences, Faculty of Science The Chinese University of Hong Kong 999077 Hong KongSchool of Life Sciences, Faculty of Science The Chinese University of Hong Kong 999077 Hong KongAbstract Early changes in astrocyte energy metabolism are associated with late‐onset Alzheimer's disease (LOAD), but the underlying mechanism remains elusive. A previous study suggested an association between a synonymous SNP (rs1012672, C→T) in LRP6 gene and LOAD; and that is indeed correlated with diminished LRP6 gene expression in the frontal cortex region. The authors show that LRP6 is a unique Wnt coreceptor on astrocytes, serving as a bimodal switch that modulates their metabolic landscapes. The Wnt‐LRP6 mediated mTOR‐AKT axis is essential for sustaining glucose metabolism. In its absence, Wnt switches to activate the LRP6‐independent Ca2+‐PKC‐NFAT axis, resulting in a transcription network that favors glutamine and branched chain amino acids (BCAAs) catabolism over glucose metabolism. Exhaustion of these raw materials essential for neurotransmitter biosynthesis and recycling results in compromised synaptic, cognitive, and memory functions; priming for early changes that are frequently found in LOAD. The authors also highlight that intranasal supplementation of glutamine and BCAAs is effective in preserving neuronal integrity and brain functions, proposing a nutrient‐based method for delaying cognitive and memory decline when LRP6 cell surface levels and functions are suboptimal.https://doi.org/10.1002/advs.202004993Alzheimer's diseaseamino acid metabolismastrocytemetabolic reprogrammingWnt signaling |
| spellingShingle | Hei‐Man Chow Jacquelyne Ka‐Li Sun Ronald P. Hart Kenneth King‐Yip Cheng Clara H. L. Hung Tsun‐Ming Lau Kin‐Ming Kwan Low‐Density Lipoprotein Receptor‐Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes Advanced Science Alzheimer's disease amino acid metabolism astrocyte metabolic reprogramming Wnt signaling |
| title | Low‐Density Lipoprotein Receptor‐Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes |
| title_full | Low‐Density Lipoprotein Receptor‐Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes |
| title_fullStr | Low‐Density Lipoprotein Receptor‐Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes |
| title_full_unstemmed | Low‐Density Lipoprotein Receptor‐Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes |
| title_short | Low‐Density Lipoprotein Receptor‐Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes |
| title_sort | low density lipoprotein receptor related protein 6 cell surface availability regulates fuel metabolism in astrocytes |
| topic | Alzheimer's disease amino acid metabolism astrocyte metabolic reprogramming Wnt signaling |
| url | https://doi.org/10.1002/advs.202004993 |
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