TY - JOUR
T1 - Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model
AU - Janczura, Karolina J.
AU - Volmar, Claude Henry
AU - Sartor, Gregory C.
AU - Rao, Sunil J.
AU - Ricciardi, Natalie R.
AU - Lambert, Guerline
AU - Brothers, Shaun P.
AU - Wahlestedt, Claes
N1 - Funding Information:
We thank the members of the Center for Therapeutic Innovation at the University of Miami Miller School of Medicine for constructive comments throughout this project; and Drs. Zane Zeier and Vladlen Slepak for revising the manuscript. This work was funded by American Heart Association Predoctoral Fellowship 17PRE33660831 (to K.J.J.); State of Florida Department of Health Ed and Ethel Moore Alzheimer’s Disease Research Program Grants 5AZ09 (to C.W.) and 6AZ08 (to C.W. and C.-H.V.); National Institute on Alcohol Abuse and Alcoholism/National Institute on Aging Grant 3R01AA023781-04S1; and NIH Grants 5R01AA023781 (to C.W.) and 5R01NS092671 (to S.P.B.). Seed funds for this project were provided internally from the University of Miami Miller School of Medicine. The NanoString experiments were conducted in the Sylvester Onco-Genomics Shared Resource. Small-molecule cell-based assays were conducted with equipment from the Sylvester Molecular Therapeutics Shared Resource. The biochemical RGFP-966 activity assay was conducted by BPS Bioscience.
Funding Information:
ACKNOWLEDGMENTS. We thank the members of the Center for Therapeutic Innovation at the University of Miami Miller School of Medicine for constructive comments throughout this project; and Drs. Zane Zeier and Vladlen Slepak for revising the manuscript. This work was funded by American Heart Association Predoctoral Fellowship 17PRE33660831 (to K.J.J.); State of Florida Department of Health Ed and Ethel Moore Alzheimer’s Disease Research Program Grants 5AZ09 (to C.W.) and 6AZ08 (to C.W. and C.-H.V.); National Institute on Alcohol Abuse and Alcoholism/National Institute on Aging Grant 3R01AA023781-04S1; and NIH Grants 5R01AA023781 (to C.W.) and 5R01NS092671 (to S.P.B.). Seed funds for this project were provided internally from the University of Miami Miller School of Medicine. The NanoString experiments were conducted in the Sylvester Onco-Genomics Shared Resource. Small-molecule cell-based assays were conducted with equipment from the Sylvester Molecular Therapeutics Shared Resource. The biochemical RGFP-966 activity assay was conducted by BPS Bioscience.
PY - 2018/11/20
Y1 - 2018/11/20
N2 - Alzheimer’s disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of β-amyloid (Aβ) plaques and accumulation of both hyperphosphorylated and acetylated tau. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 silencing, increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-associated sites, reduces β-secretase cleavage of the amyloid precursor protein (APP), and decreases Aβ1–42 accumulation in HEK-293 cells overexpressing APP with the double Swedish mutation (HEK/APPsw). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathological tau phosphorylation at Thr181, Ser202, and Ser396, increases levels of the Aβ degrading enzyme Neprilysin in plasma, decreases Aβ1–42 protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases Aβ1–42 accumulation and both tau acetylation and phosphorylation at disease residues in neurons derived from induced pluripotent stem cells obtained from APOEe4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins associated with AD pathophysiology, supporting the notion that HDAC3 may be a disease-modifying therapeutic target.
AB - Alzheimer’s disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of β-amyloid (Aβ) plaques and accumulation of both hyperphosphorylated and acetylated tau. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 silencing, increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-associated sites, reduces β-secretase cleavage of the amyloid precursor protein (APP), and decreases Aβ1–42 accumulation in HEK-293 cells overexpressing APP with the double Swedish mutation (HEK/APPsw). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathological tau phosphorylation at Thr181, Ser202, and Ser396, increases levels of the Aβ degrading enzyme Neprilysin in plasma, decreases Aβ1–42 protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases Aβ1–42 accumulation and both tau acetylation and phosphorylation at disease residues in neurons derived from induced pluripotent stem cells obtained from APOEe4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins associated with AD pathophysiology, supporting the notion that HDAC3 may be a disease-modifying therapeutic target.
KW - Alzheimer’s disease
KW - Epigenetics
KW - HDACs
KW - Histone deacetylase 3 inhibitor
KW - Tau posttranslational modifications
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U2 - 10.1073/pnas.1805436115
DO - 10.1073/pnas.1805436115
M3 - Article
C2 - 30397132
AN - SCOPUS:85056788613
VL - 115
SP - E11148-E11157
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 47
ER -