期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 47, 页码 E11148-E11157出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1805436115
关键词
Alzheimer's disease; histone deacetylase 3 inhibitor; epigenetics; tau posttranslational modifications; HDACs
资金
- American Heart Association [17PRE33660831]
- State of Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program [5AZ09, 6AZ08]
- National Institute on Alcohol Abuse and Alcoholism/National Institute on Aging [3R01AA023781-04S1]
- NIH [5R01AA023781, 5R01NS092671]
- University of Miami Miller School of Medicine
Alzheimer's disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of beta-amyloid (A beta) 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 beta-secretase cleavage of the amyloid precursor protein (APP), and decreases A beta(1-42) accumulation in HEK-293 cells overexpressing APP with the double Swedish mutation (HEK/APP(sw)). 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 Thr(181), Ser(202), and Ser(396), increases levels of the A beta degrading enzyme Neprilysin in plasma, decreases A beta(1-42) protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases A beta(1-42) accumulation and both tau acetylation and phosphorylation at disease residues in neurons derived from induced pluripotent stem cells obtained from APOE epsilon 4-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.
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