APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology
Abstract Background Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer’s Disease (AD). However, i...
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2025-01-01
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| Series: | Molecular Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s13024-024-00793-x |
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| author | Kristine M. Tran Nellie E. Kwang Claire A. Butler Angela Gomez-Arboledas Shimako Kawauchi Cassandra Mar Donna Chao Rocio A. Barahona Celia Da Cunha Kate I. Tsourmas Zechuan Shi Shuling Wang Sherilyn Collins Amber Walker Kai-Xuan Shi Joshua A. Alcantara Jonathan Neumann Duc M. Duong Nicholas T. Seyfried Andrea J. Tenner Frank M. LaFerla Lindsay A. Hohsfield Vivek Swarup Grant R. MacGregor Kim N. Green |
| author_facet | Kristine M. Tran Nellie E. Kwang Claire A. Butler Angela Gomez-Arboledas Shimako Kawauchi Cassandra Mar Donna Chao Rocio A. Barahona Celia Da Cunha Kate I. Tsourmas Zechuan Shi Shuling Wang Sherilyn Collins Amber Walker Kai-Xuan Shi Joshua A. Alcantara Jonathan Neumann Duc M. Duong Nicholas T. Seyfried Andrea J. Tenner Frank M. LaFerla Lindsay A. Hohsfield Vivek Swarup Grant R. MacGregor Kim N. Green |
| author_sort | Kristine M. Tran |
| collection | DOAJ |
| description | Abstract Background Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer’s Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects. Methods We introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain’s response to plaques and tau. Results In 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice. Conclusions These findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming. Graphical Abstract |
| format | Article |
| id | doaj-art-64c1d0d86c08473db659bf70e4f03c40 |
| institution | Kabale University |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Molecular Neurodegeneration |
| spelling | doaj-art-64c1d0d86c08473db659bf70e4f03c402025-01-26T12:52:29ZengBMCMolecular Neurodegeneration1750-13262025-01-0120114010.1186/s13024-024-00793-xAPOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathologyKristine M. Tran0Nellie E. Kwang1Claire A. Butler2Angela Gomez-Arboledas3Shimako Kawauchi4Cassandra Mar5Donna Chao6Rocio A. Barahona7Celia Da Cunha8Kate I. Tsourmas9Zechuan Shi10Shuling Wang11Sherilyn Collins12Amber Walker13Kai-Xuan Shi14Joshua A. Alcantara15Jonathan Neumann16Duc M. Duong17Nicholas T. Seyfried18Andrea J. Tenner19Frank M. LaFerla20Lindsay A. Hohsfield21Vivek Swarup22Grant R. MacGregor23Kim N. Green24Department of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaInstitute for Memory Impairments and Neurological Disorders, University of CaliforniaInstitute for Memory Impairments and Neurological Disorders, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaInstitute for Memory Impairments and Neurological Disorders, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaTransgenic Mouse Facility, ULAR, Office of Research, University of CaliforniaTransgenic Mouse Facility, ULAR, Office of Research, University of CaliforniaTransgenic Mouse Facility, ULAR, Office of Research, University of CaliforniaTransgenic Mouse Facility, ULAR, Office of Research, University of CaliforniaTransgenic Mouse Facility, ULAR, Office of Research, University of CaliforniaTransgenic Mouse Facility, ULAR, Office of Research, University of CaliforniaARCProteomicsGoizueta Alzheimer’s Disease Research Center, Emory University School of MedicineDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaTransgenic Mouse Facility, ULAR, Office of Research, University of CaliforniaDepartment of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of CaliforniaAbstract Background Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer’s Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects. Methods We introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain’s response to plaques and tau. Results In 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice. Conclusions These findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming. Graphical Abstracthttps://doi.org/10.1186/s13024-024-00793-xAPOE ChristchurchPS195xFADMicrogliaDAMAmyloid |
| spellingShingle | Kristine M. Tran Nellie E. Kwang Claire A. Butler Angela Gomez-Arboledas Shimako Kawauchi Cassandra Mar Donna Chao Rocio A. Barahona Celia Da Cunha Kate I. Tsourmas Zechuan Shi Shuling Wang Sherilyn Collins Amber Walker Kai-Xuan Shi Joshua A. Alcantara Jonathan Neumann Duc M. Duong Nicholas T. Seyfried Andrea J. Tenner Frank M. LaFerla Lindsay A. Hohsfield Vivek Swarup Grant R. MacGregor Kim N. Green APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology Molecular Neurodegeneration APOE Christchurch PS19 5xFAD Microglia DAM Amyloid |
| title | APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology |
| title_full | APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology |
| title_fullStr | APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology |
| title_full_unstemmed | APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology |
| title_short | APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology |
| title_sort | apoe christchurch enhances a disease associated microglial response to plaque but suppresses response to tau pathology |
| topic | APOE Christchurch PS19 5xFAD Microglia DAM Amyloid |
| url | https://doi.org/10.1186/s13024-024-00793-x |
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