TY - JOUR
T1 - APOE genotype regulates pathology and disease progression in synucleinopathy
AU - Davis, Albert A.
AU - Inman, Casey E.
AU - Wargel, Zachary M.
AU - Dube, Umber
AU - Freeberg, Brittany M.
AU - Galluppi, Alexander
AU - Haines, Jessica N.
AU - Dhavale, Dhruva D.
AU - Miller, Rebecca
AU - Choudhury, Fahim A.
AU - Sullivan, Patrick M.
AU - Cruchaga, Carlos
AU - Perlmutter, Joel S.
AU - Ulrich, Jason D.
AU - Benitez, Bruno A.
AU - Kotzbauer, Paul T.
AU - Holtzman, David M.
N1 - Funding Information:
This work was supported by an American Academy of Neurology/American Brain Foundation Clinical Research Training Fellowship (to A.A.D.); the BrightFocus Foundation (to A.A.D.); the Mary E. Groff Charitable Trust (to A.A.D.); the Dobbins Family Fund (to A.A.D.); the Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund; to J.S.P.); the Riney Foundation (to J.S.P.); the American Parkinson Disease Association (APDA) (to J.S.P.); the Greater St. Louis Chapter of the APDA (to J.S.P.); the JPB Foundation (to D.M.H.); and NIH K08NS101118 (to A.A.D.), R01AG044546 (to C.C.), RF1AG053303 (to C.C.), RF1AG058501 (to C.C.), U01AG052411 (to C.C.), U01AG058922 (to C.C.), NS075321 (to J.S.P.), NS097799 (to P.T.K.), R01NS090934 (to D.M.H.), and R01 AG047644 (to D.M.H.).
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
PY - 2020/2/5
Y1 - 2020/2/5
N2 - Apolipoprotein E (APOE) ε4 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 ε4 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 ε4/ε4 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 ε4 exacerbates pathology, and suggest that APOE ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.
AB - Apolipoprotein E (APOE) ε4 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 ε4 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 ε4/ε4 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 ε4 exacerbates pathology, and suggest that APOE ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.
UR - http://www.scopus.com/inward/record.url?scp=85079051741&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aay3069
DO - 10.1126/scitranslmed.aay3069
M3 - Article
C2 - 32024799
AN - SCOPUS:85079051741
SN - 1946-6234
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 529
M1 - eaay3069
ER -