Inhibition of HDAC3 Activity with RGFP-966 Alleviates Memory Impairment in the Triple Transgenic Alzheimer’s Disease Mouse Model and Reverses Disease-related Pathological Hallmarks in Patient-derived Neurons
Inhibition of HDAC3 Activity with RGFP-966 Alleviates Memory Impairment in the Triple Transgenic Alzheimer's Disease Mouse Model and Reverses Disease-related Pathological Hallmarks in Patient-derived Neurons K. Janczura1, C.-H. Volmar1, N. Riccardi1, S.Brothers1, G.Sartor1, C.Wahlestedt1 1University of Miami Miller School of Medicine, Center for Therapeutic Innovation (CTI), Department of Psychiatry & Behavioral Sciences, Miami, FL 33136
Alzheimer's disease (AD) is characterized by brain deposition of β-amyloid (Aβ) plaques and hyperphosphorylated and acetylated tau. Histone deacetylase (HDAC) enzymes remove acetyl groups from histones and modify chromatin transcriptional activity. Increased HDAC activity has been associated with the progression of AD. We hypothesized that inhibition of HDAC3 would present a favorable anti-AD profile. RGFP-966, a brain-penetrant, HDAC3 inhibitor increases histone H3 and H4 acetylation on three lysine (K) residues associated with memory and cognition. Sub-chronic administration of RGFP-966 improves short-term and spatial recognition memory, improves general locomotor coordination and decreases fatigue in the triple transgenic (APPsw/PS1M146V/TauP301L) mouse model of AD (3xTg-AD). RGFP-966 decreases tau hyperphosphorylation at disease-relevant sites (Thr181, Ser202, Ser396) in different brain regions of 3x-Tg AD mice. Inhibition of HDAC3 decreases the accumulation of toxic Aβ species in the brain and in peripheral blood mononuclear cells (PBMCs). These beneficial effects of RGFP-966 on Aβ are attributed to a significant decrease of BACE1 expression (an Aβ generating protease) in the brain, and a significant increase of the Aβ degrading protease Neprilysin in the periphery. We also show that HDAC3 activity is significantly increased in neurons derived from two lines of induced pluripotent stem cells (iPSCs) obtained from APOEε4-carrying AD patients, compared to healthy age-matched controls. RGFP-966 decreases HDAC3 activity, Aβ accumulation, tau phosphorylation and tau acetylation to levels comparable to controls. Taken together, our data suggest that HDAC3 inhibition reverses AD-like pathology and holds potential for the development of novel disease modifying AD therapeutics.
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