Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal Transport
The amyloid precursor protein (APP) is a key molecular component of Alzheimer’s disease (AD) pathogenesis. Proteolytic APP processing generates various cleavage products, including extracellular amyloid beta (Aβ) and the cytoplasmic APP intracellular domain (AICD). Although the role of AICD in the a...
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MDPI AG
2023-10-01
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| author | Svenja König Nadine Schmidt Karin Bechberger Sarah Morris Mercedes Priego Hannah Zaky Yuyu Song Jan Pielage Silke Brunholz Scott T. Brady Stefan Kins Gerardo Morfini |
| author_facet | Svenja König Nadine Schmidt Karin Bechberger Sarah Morris Mercedes Priego Hannah Zaky Yuyu Song Jan Pielage Silke Brunholz Scott T. Brady Stefan Kins Gerardo Morfini |
| author_sort | Svenja König |
| collection | DOAJ |
| description | The amyloid precursor protein (APP) is a key molecular component of Alzheimer’s disease (AD) pathogenesis. Proteolytic APP processing generates various cleavage products, including extracellular amyloid beta (Aβ) and the cytoplasmic APP intracellular domain (AICD). Although the role of AICD in the activation of kinase signaling pathways is well established in the context of full-length APP, little is known about intracellular effects of the AICD fragment, particularly within discrete neuronal compartments. Deficits in fast axonal transport (FAT) and axonopathy documented in AD-affected neurons prompted us to evaluate potential axon-autonomous effects of the AICD fragment for the first time. Vesicle motility assays using the isolated squid axoplasm preparation revealed inhibition of FAT by AICD. Biochemical experiments linked this effect to aberrant activation of selected axonal kinases and heightened phosphorylation of the anterograde motor protein conventional kinesin, consistent with precedents showing phosphorylation-dependent regulation of motors proteins powering FAT. Pharmacological inhibitors of these kinases alleviated the AICD inhibitory effect on FAT. Deletion experiments indicated this effect requires a sequence encompassing the NPTY motif in AICD and interacting axonal proteins containing a phosphotyrosine-binding domain. Collectively, these results provide a proof of principle for axon-specific effects of AICD, further suggesting a potential mechanistic framework linking alterations in APP processing, FAT deficits, and axonal pathology in AD. |
| first_indexed | 2024-03-10T21:47:35Z |
| format | Article |
| id | doaj.art-6703bde0bb5c498e83438eabd66e9cf8 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T21:47:35Z |
| publishDate | 2023-10-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-6703bde0bb5c498e83438eabd66e9cf82023-11-19T14:13:19ZengMDPI AGCells2073-44092023-10-011219240310.3390/cells12192403Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal TransportSvenja König0Nadine Schmidt1Karin Bechberger2Sarah Morris3Mercedes Priego4Hannah Zaky5Yuyu Song6Jan Pielage7Silke Brunholz8Scott T. Brady9Stefan Kins10Gerardo Morfini11Department for Human Biology and Human Genetics, University of Kaiserslautern-Landau, 67663 Kaiserslautern, GermanyDepartment for Human Biology and Human Genetics, University of Kaiserslautern-Landau, 67663 Kaiserslautern, GermanyDepartment for Human Biology and Human Genetics, University of Kaiserslautern-Landau, 67663 Kaiserslautern, GermanyDepartment of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USAMarine Biological Laboratory, Woods Hole, MA 02543, USADepartment of Zoology, University of Kaiserslautern-Landau, 67663 Kaiserslautern, GermanyDepartment for Human Biology and Human Genetics, University of Kaiserslautern-Landau, 67663 Kaiserslautern, GermanyDepartment of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USADepartment for Human Biology and Human Genetics, University of Kaiserslautern-Landau, 67663 Kaiserslautern, GermanyDepartment of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USAThe amyloid precursor protein (APP) is a key molecular component of Alzheimer’s disease (AD) pathogenesis. Proteolytic APP processing generates various cleavage products, including extracellular amyloid beta (Aβ) and the cytoplasmic APP intracellular domain (AICD). Although the role of AICD in the activation of kinase signaling pathways is well established in the context of full-length APP, little is known about intracellular effects of the AICD fragment, particularly within discrete neuronal compartments. Deficits in fast axonal transport (FAT) and axonopathy documented in AD-affected neurons prompted us to evaluate potential axon-autonomous effects of the AICD fragment for the first time. Vesicle motility assays using the isolated squid axoplasm preparation revealed inhibition of FAT by AICD. Biochemical experiments linked this effect to aberrant activation of selected axonal kinases and heightened phosphorylation of the anterograde motor protein conventional kinesin, consistent with precedents showing phosphorylation-dependent regulation of motors proteins powering FAT. Pharmacological inhibitors of these kinases alleviated the AICD inhibitory effect on FAT. Deletion experiments indicated this effect requires a sequence encompassing the NPTY motif in AICD and interacting axonal proteins containing a phosphotyrosine-binding domain. Collectively, these results provide a proof of principle for axon-specific effects of AICD, further suggesting a potential mechanistic framework linking alterations in APP processing, FAT deficits, and axonal pathology in AD.https://www.mdpi.com/2073-4409/12/19/2403Alzheimer’s diseaseAPPAICDkinasesNPTY |
| spellingShingle | Svenja König Nadine Schmidt Karin Bechberger Sarah Morris Mercedes Priego Hannah Zaky Yuyu Song Jan Pielage Silke Brunholz Scott T. Brady Stefan Kins Gerardo Morfini Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal Transport Cells Alzheimer’s disease APP AICD kinases NPTY |
| title | Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal Transport |
| title_full | Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal Transport |
| title_fullStr | Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal Transport |
| title_full_unstemmed | Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal Transport |
| title_short | Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal Transport |
| title_sort | axon autonomous effects of the amyloid precursor protein intracellular domain aicd on kinase signaling and fast axonal transport |
| topic | Alzheimer’s disease APP AICD kinases NPTY |
| url | https://www.mdpi.com/2073-4409/12/19/2403 |
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