Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE
Abstract APOE is a major genetic factor in late-onset Alzheimer’s disease (LOAD), with APOE4 increasing risk, APOE3 acting as neutral, and APOE2 offering protection. APOE also plays key role in lipid metabolism, affecting both peripheral and central systems, particularly in lipoprotein metabolism in...
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BMC
2024-09-01
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| Series: | Cell Communication and Signaling |
| Online Access: | https://doi.org/10.1186/s12964-024-01832-2 |
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| author | Metin Yesiltepe Tao Yin Marc Tambini Hanmei Bao Meixia Pan Cristina d’Abramo Luca Giliberto Xianlin Han Luciano D’Adamio |
| author_facet | Metin Yesiltepe Tao Yin Marc Tambini Hanmei Bao Meixia Pan Cristina d’Abramo Luca Giliberto Xianlin Han Luciano D’Adamio |
| author_sort | Metin Yesiltepe |
| collection | DOAJ |
| description | Abstract APOE is a major genetic factor in late-onset Alzheimer’s disease (LOAD), with APOE4 increasing risk, APOE3 acting as neutral, and APOE2 offering protection. APOE also plays key role in lipid metabolism, affecting both peripheral and central systems, particularly in lipoprotein metabolism in triglyceride and cholesterol regulation. APOE2 is linked to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia due to impaired binding to Low-Density Lipoproteins receptors. To explore the impact of human APOE isoforms on LOAD and lipid metabolism, we developed Long-Evans rats with human APOE2, APOE3, or APOE4 in place of rat Apoe. These rats were crossed with those carrying a humanized App allele to express human Aβ, which is more aggregation-prone than rodent Aβ, enabling the study of human APOE-human Aβ interactions. In this study, we focused on 80-day-old adolescent rats to analyze early changes that may be associated with the later development of LOAD. We found that APOE2 hAβ rats had the highest levels of APOE in serum and brain, with no significant transcriptional differences among isoforms, suggesting variations in protein translation or stability. Aβ43 levels were significantly higher in male APOE4 hAβ rats compared to APOE2 hAβ rats. However, no differences in Tau or phosphorylated Tau levels were observed across the APOE isoforms. Neuroinflammation analysis revealed lower levels of IL13, IL4 and IL5 in APOE2 hAβ males compared to APOE4 hAβ males. Neuronal transmission and plasticity tests using field Input-Output (I/O) and long-term potentiation (LTP) recordings showed increased excitability in all APOE-carrying rats, with LTP deficits in APOE2 hAβ and APOE4 hAβ rats compared to Apoe hAβ and APOE3 hAβ rats. Additionally, a lipidomic analysis of 222 lipid molecular species in serum samples showed that APOE2 hAβ rats displayed elevated triglycerides and cholesterol, making them a valuable model for studying HLP. These rats also exhibited elevated levels of phosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine. Minimal differences in lipid profiles between APOE3 hAβ and APOE4 hAβ rats reflect findings from mouse models. Future studies will include comprehensive lipidomic analyses in various CNS regions and at older ages to further validate these models and explore the effects of APOE isoforms on lipid metabolism in relation to AD pathology. |
| format | Article |
| id | doaj-art-98bd553d104c475d991338763f87e570 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2024-09-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-98bd553d104c475d991338763f87e5702025-01-05T12:41:42ZengBMCCell Communication and Signaling1478-811X2024-09-0122113010.1186/s12964-024-01832-2Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOEMetin Yesiltepe0Tao Yin1Marc Tambini2Hanmei Bao3Meixia Pan4Cristina d’Abramo5Luca Giliberto6Xianlin Han7Luciano D’Adamio8Department of Pharmacology, Physiology & Neuroscience New Jersey Medical School, The State University of New Jersey, RutgersDepartment of Pharmacology, Physiology & Neuroscience New Jersey Medical School, The State University of New Jersey, RutgersDepartment of Pharmacology, Physiology & Neuroscience New Jersey Medical School, The State University of New Jersey, RutgersBarshop Institute for Longevity and Aging Studies, University of Texas Health San AntonioBarshop Institute for Longevity and Aging Studies, University of Texas Health San AntonioLitwin-Zucker Center for the Study of Alzheimer’s Disease and Memory Disorders, Feinstein Institutes for Medical Research, Institute of Molecular MedicineLitwin-Zucker Center for the Study of Alzheimer’s Disease and Memory Disorders, Feinstein Institutes for Medical Research, Institute of Molecular MedicineBarshop Institute for Longevity and Aging Studies, University of Texas Health San AntonioDepartment of Pharmacology, Physiology & Neuroscience New Jersey Medical School, The State University of New Jersey, RutgersAbstract APOE is a major genetic factor in late-onset Alzheimer’s disease (LOAD), with APOE4 increasing risk, APOE3 acting as neutral, and APOE2 offering protection. APOE also plays key role in lipid metabolism, affecting both peripheral and central systems, particularly in lipoprotein metabolism in triglyceride and cholesterol regulation. APOE2 is linked to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia due to impaired binding to Low-Density Lipoproteins receptors. To explore the impact of human APOE isoforms on LOAD and lipid metabolism, we developed Long-Evans rats with human APOE2, APOE3, or APOE4 in place of rat Apoe. These rats were crossed with those carrying a humanized App allele to express human Aβ, which is more aggregation-prone than rodent Aβ, enabling the study of human APOE-human Aβ interactions. In this study, we focused on 80-day-old adolescent rats to analyze early changes that may be associated with the later development of LOAD. We found that APOE2 hAβ rats had the highest levels of APOE in serum and brain, with no significant transcriptional differences among isoforms, suggesting variations in protein translation or stability. Aβ43 levels were significantly higher in male APOE4 hAβ rats compared to APOE2 hAβ rats. However, no differences in Tau or phosphorylated Tau levels were observed across the APOE isoforms. Neuroinflammation analysis revealed lower levels of IL13, IL4 and IL5 in APOE2 hAβ males compared to APOE4 hAβ males. Neuronal transmission and plasticity tests using field Input-Output (I/O) and long-term potentiation (LTP) recordings showed increased excitability in all APOE-carrying rats, with LTP deficits in APOE2 hAβ and APOE4 hAβ rats compared to Apoe hAβ and APOE3 hAβ rats. Additionally, a lipidomic analysis of 222 lipid molecular species in serum samples showed that APOE2 hAβ rats displayed elevated triglycerides and cholesterol, making them a valuable model for studying HLP. These rats also exhibited elevated levels of phosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine. Minimal differences in lipid profiles between APOE3 hAβ and APOE4 hAβ rats reflect findings from mouse models. Future studies will include comprehensive lipidomic analyses in various CNS regions and at older ages to further validate these models and explore the effects of APOE isoforms on lipid metabolism in relation to AD pathology.https://doi.org/10.1186/s12964-024-01832-2 |
| spellingShingle | Metin Yesiltepe Tao Yin Marc Tambini Hanmei Bao Meixia Pan Cristina d’Abramo Luca Giliberto Xianlin Han Luciano D’Adamio Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE Cell Communication and Signaling |
| title | Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE |
| title_full | Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE |
| title_fullStr | Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE |
| title_full_unstemmed | Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE |
| title_short | Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE |
| title_sort | analysis of early effects of human apoe isoforms on alzheimer s disease and type iii hyperlipoproteinemia pathways using knock in rat models with humanized app and apoe |
| url | https://doi.org/10.1186/s12964-024-01832-2 |
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