TY - JOUR
T1 - Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model
AU - Litvinchuk, Alexandra
AU - Huynh, Tien Phat V.
AU - Shi, Yang
AU - Jackson, Rosemary J.
AU - Finn, Mary B.
AU - Manis, Melissa
AU - Francis, Caroline M.
AU - Tran, Ainsley C.
AU - Sullivan, Patrick M.
AU - Ulrich, Jason D.
AU - Hyman, Bradley T.
AU - Cole, Tracy
AU - Holtzman, David M.
N1 - Funding Information:
This work was supported by NIH grants AG047644 (D.M.H. and B.T.H.), NS090932 (D.M.H.), the JPB Foundation (D.M.H.), and the Rainwater Consortium (D.M.H.). The graphical image was acquired with BioRender Software.
Publisher Copyright:
© 2021 American Neurological Association
PY - 2021/5
Y1 - 2021/5
N2 - Objective: Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-β deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration. Methods: Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age. Results: Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice. Interpretation: We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952–966.
AB - Objective: Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-β deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration. Methods: Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age. Results: Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice. Interpretation: We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952–966.
UR - http://www.scopus.com/inward/record.url?scp=85101586846&partnerID=8YFLogxK
U2 - 10.1002/ana.26043
DO - 10.1002/ana.26043
M3 - Article
C2 - 33550655
AN - SCOPUS:85101586846
SN - 0364-5134
VL - 89
SP - 952
EP - 966
JO - Annals of neurology
JF - Annals of neurology
IS - 5
ER -