APOE genotype regulates pathology and disease progression in synucleinopathy
| العنوان: | APOE genotype regulates pathology and disease progression in synucleinopathy |
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| المؤلفون: | Paul T. Kotzbauer, Umber Dube, Jason D. Ulrich, Patrick Sullivan, Brittany M. Freeberg, Alexander Galluppi, Carlos Cruchaga, Jessica N. Haines, Joel S. Perlmutter, David M. Holtzman, Rebecca L. Miller, Bruno A. Benitez, Casey E. Inman, Dhruva Dhavale, Fahim A. Choudhury, Zachary M. Wargel, Albert A. Davis |
| المصدر: | Science Translational Medicine. 12 |
| بيانات النشر: | American Association for the Advancement of Science (AAAS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Apolipoprotein E, Synucleinopathies, Genetically modified mouse, Pathology, medicine.medical_specialty, business.industry, Neurodegeneration, Substantia nigra, General Medicine, medicine.disease, Genotype, medicine, Immunohistochemistry, Cognitive decline, business |
| الوصف: | Apolipoprotein E (APOE) e4 genotype is associated with increased risk of dementia in Parkinson's disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. APOE e4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether APOE genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on Apoe knockout (A53T/EKO) or human APOE knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes. In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice. In two separate cohorts of human patients with PD, APOE e4/e4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that APOE genotype directly regulates αSyn pathology independent of its established effects on Aβ and tau, corroborate the finding that APOE e4 exacerbates pathology, and suggest that APOE e2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies. |
| تدمد: | 1946-6242 1946-6234 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::fcb98539a80a5bb7fef8aaf813a8b30d https://doi.org/10.1126/scitranslmed.aay3069 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........fcb98539a80a5bb7fef8aaf813a8b30d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19466242 19466234 |
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