| First Author | Davis AA | Year | 2020 |
| Journal | Sci Transl Med | Volume | 12 |
| Issue | 529 | PubMed ID | 32024799 |
| Mgi Jnum | J:285310 | Mgi Id | MGI:6390622 |
| Doi | 10.1126/scitranslmed.aay3069 | Citation | Davis AA, et al. (2020) APOE genotype regulates pathology and disease progression in synucleinopathy. Sci Transl Med 12(529) |
| abstractText | Apolipoprotein E (APOE) epsilon4 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 alpha-synuclein (alphaSyn), amyloid-beta (Abeta), and tau pathologies. APOE epsilon4 exacerbates brain Abeta pathology, as well as tau pathology, but it is not clear whether APOE genotype independently regulates alphaSyn pathology. In this study, we generated A53T alphaSyn 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 alphaSyn compared to A53T/EKO and A53T/E3; detergent-insoluble alphaSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated alphaSyn 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 alphaSyn spreading, striatal injection of alphaSyn preformed fibrils induced greater accumulation of alphaSyn 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 epsilon4/epsilon4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that APOE genotype directly regulates alphaSyn pathology independent of its established effects on Abeta and tau, corroborate the finding that APOE epsilon4 exacerbates pathology, and suggest that APOE epsilon2 may protect against alphaSyn aggregation and neurodegeneration in synucleinopathies. |
