Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome
Abstract Introduction Retromer complex proteins are decreased in Down syndrome (DS) brains and correlate inversely with brain amyloidosis. However, whether retromer dysfunction contributes to the amyloid beta (Aβ) and tau neuropathology of DS remains unknown. Methods Human trisomic induced Pluripote...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/trc2.12334 |
| _version_ | 1797948990773264384 |
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| author | Mary Elizabeth Curtis Tiffany Smith Benjamin E. Blass Domenico Praticò |
| author_facet | Mary Elizabeth Curtis Tiffany Smith Benjamin E. Blass Domenico Praticò |
| author_sort | Mary Elizabeth Curtis |
| collection | DOAJ |
| description | Abstract Introduction Retromer complex proteins are decreased in Down syndrome (DS) brains and correlate inversely with brain amyloidosis. However, whether retromer dysfunction contributes to the amyloid beta (Aβ) and tau neuropathology of DS remains unknown. Methods Human trisomic induced Pluripotent Stem Cells (iPSCs) and isogenic controls were differentiated into forebrain neurons, and changes in retromer proteins, tau phosphorylated epitopes, and Aβ levels were assessed in euploid and trisomic neurons using western blot and enzyme‐linked immunosorbent assay (ELISA). Genetic overexpression and pharmacological retromer stabilization were used to determine the functional role of the retromer complex system in modulating amyloid and tau pathology. Results Trisomic neurons developed age‐dependent retromer core protein deficiency associated with accumulation of Aβ peptides and phosphorylated tau isoforms. Enhancing retromer function through overexpression or pharmacological retromer stabilization reduced amyloid and tau pathology in trisomic neurons. However, the effect was greater using a pharmacological approach, suggesting that targeting the complex stability may be more effective in addressing this neuropathology in DS. Discussion Our results demonstrate that the retromer complex is directly involved in the development of the neuropathologic phenotype in DS, and that pharmacological stabilization of the complex should be considered as a novel therapeutic tool in people with DS. |
| first_indexed | 2024-04-10T21:52:17Z |
| format | Article |
| id | doaj.art-762a171bcdf54b88a842a1156a594ce7 |
| institution | Directory Open Access Journal |
| issn | 2352-8737 |
| language | English |
| last_indexed | 2024-04-10T21:52:17Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| spelling | doaj.art-762a171bcdf54b88a842a1156a594ce72023-01-18T11:41:04ZengWileyAlzheimer’s & Dementia: Translational Research & Clinical Interventions2352-87372022-01-0181n/an/a10.1002/trc2.12334Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndromeMary Elizabeth Curtis0Tiffany Smith1Benjamin E. Blass2Domenico Praticò3Alzheimer's Center at Temple Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USAAlzheimer's Center at Temple Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USASchool of Pharmacy Temple University Philadelphia Pennsylvania USAAlzheimer's Center at Temple Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USAAbstract Introduction Retromer complex proteins are decreased in Down syndrome (DS) brains and correlate inversely with brain amyloidosis. However, whether retromer dysfunction contributes to the amyloid beta (Aβ) and tau neuropathology of DS remains unknown. Methods Human trisomic induced Pluripotent Stem Cells (iPSCs) and isogenic controls were differentiated into forebrain neurons, and changes in retromer proteins, tau phosphorylated epitopes, and Aβ levels were assessed in euploid and trisomic neurons using western blot and enzyme‐linked immunosorbent assay (ELISA). Genetic overexpression and pharmacological retromer stabilization were used to determine the functional role of the retromer complex system in modulating amyloid and tau pathology. Results Trisomic neurons developed age‐dependent retromer core protein deficiency associated with accumulation of Aβ peptides and phosphorylated tau isoforms. Enhancing retromer function through overexpression or pharmacological retromer stabilization reduced amyloid and tau pathology in trisomic neurons. However, the effect was greater using a pharmacological approach, suggesting that targeting the complex stability may be more effective in addressing this neuropathology in DS. Discussion Our results demonstrate that the retromer complex is directly involved in the development of the neuropathologic phenotype in DS, and that pharmacological stabilization of the complex should be considered as a novel therapeutic tool in people with DS.https://doi.org/10.1002/trc2.12334Alzheimer´s diseaseAβDown syndromeretromertau |
| spellingShingle | Mary Elizabeth Curtis Tiffany Smith Benjamin E. Blass Domenico Praticò Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome Alzheimer’s & Dementia: Translational Research & Clinical Interventions Alzheimer´s disease Aβ Down syndrome retromer tau |
| title | Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome |
| title_full | Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome |
| title_fullStr | Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome |
| title_full_unstemmed | Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome |
| title_short | Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome |
| title_sort | dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of down syndrome |
| topic | Alzheimer´s disease Aβ Down syndrome retromer tau |
| url | https://doi.org/10.1002/trc2.12334 |
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