Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model

Karolina J. Janczura, Claude Henry Volmar, Gregory C. Sartor, Sunil J. Rao, Natalie R. Ricciardi, Guerline Lambert, Shaun P. Brothers, Claes Wahlestedt

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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 Aβ142 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 Aβ142 protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases Aβ142 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.

Original languageEnglish (US)
Pages (from-to)E11148-E11157
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number47
DOIs
StatePublished - Nov 20 2018

Keywords

  • Alzheimer’s disease
  • Epigenetics
  • HDACs
  • Histone deacetylase 3 inhibitor
  • Tau posttranslational modifications

ASJC Scopus subject areas

  • General

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