Nearly two-thirds of Alzheimer's disease (AD) patients are women. Therapeutics for women are critical to lowering their elevated risk of developing this major cause of adult dementia. Moreover, targeting epigenetic processes such as histone acetylation that regulate multiple cellular pathways is advantageous given the multifactorial nature of AD. Histone acetylation takes part in memory consolidation, and its disruption is linked to AD.
Objective
Determine whether the investigational drug RG2833 has repurposing potential for AD. RG2833 is a histone deacetylase HDAC1/3 inhibitor that is orally bioavailable and permeates the blood-brain-barrier.
Methods
RG2833 effects were determined on cognition, transcriptome, and AD-like pathology in 11-month TgF344-AD female and male rats. Treatment started early in the course of pathology when therapeutic intervention is predicted to be most effective.
Results
RG2833-treatment of 11-month TgF344-AD rats: (1) Significantly improved hippocampal-dependent spatial memory in females but not males. (2) Upregulated expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation in females. Remarkably, out of 17,168 genes analyzed for each sex, no significant changes in gene expression were detected in males at p < 0.05, false discovery rate <0.05, and fold-change equal or > 1.5. (3) Failed to improve amyloid beta accumulation and microgliosis in female and male TgF344-AD rats.
Conclusions
Our study highlights the potential of histone-modifying therapeutics such as RG2833 to improve cognitive behavior and drive the expression of immediate early, synaptic plasticity and memory consolidation genes, especially in female AD patients.
Nikolac PerkovicMVidetic PaskaAKonjevodM, et al.Epigenetics of Alzheimer's disease. Biomolecules2021; 11: 195.
2.
GraffJTsaiLH. The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol2013; 53: 311–330.
3.
PellegriniCPirazziniCSalaC, et al.A meta-analysis of brain DNA methylation across sex, age, and Alzheimer's disease points for accelerated epigenetic aging in neurodegeneration. Front Aging Neurosci2021; 13: 639428.
4.
AltunaMUrdánoz-CasadoASánchez-Ruiz de GordoaJ, et al.DNA Methylation signature of human hippocampus in Alzheimer's disease is linked to neurogenesis. Clin Epigenetics2019; 11: 91.
5.
WeiXZhangLZengY. DNA Methylation in Alzheimer's disease: in brain and peripheral blood. Mech Ageing Dev2020; 191: 111319.
6.
SmithARSmithRGMacdonaldR, et al.The histone modification H3K4me3 is altered at the ANK1 locus in Alzheimer's disease brain. Future Sci OA2021; 7: FSO665.
7.
MarziSJLeungSKRibarskaT, et al.A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nat Neurosci2018; 21: 1618–1627.
8.
SchuellerEPaivaIBlancF, et al.Dysregulation of histone acetylation pathways in hippocampus and frontal cortex of Alzheimer's disease patients. Eur Neuropsychopharmacol2020; 33: 101–116.
9.
WoodIC. The contribution and therapeutic potential of epigenetic modifications in Alzheimer's disease. Front Neurosci2018; 12: 649.
10.
HaggartySJTsaiLH. Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticity. Neurobiol Learn Mem2011; 96: 41–52.
11.
SantanaDASmithMACChenES. Histone modifications in Alzheimer's disease. Genes (Basel)2023; 14: 347.
12.
QinYYangPHeW, et al.Novel histone post-translational modifications in Alzheimer's disease: current advances and implications. Clin Epigenetics2024; 16: 39.
13.
MahadyLNadeemMMalek-AhmadiM, et al.Frontal cortex epigenetic dysregulation during the progression of Alzheimer's disease. J Alzheimers Dis2018; 62: 115–131.
14.
GengFZhaoNChenX, et al.Transcriptome analysis identifies the role of class I histone deacetylase in Alzheimer's disease. Heliyon2023; 9: e18008.
15.
SantanaDABedratAPugaRD, et al.The role of H3K9 acetylation and gene expression in different brain regions of Alzheimer's disease patients. Epigenomics2022; 14: 651–670.
16.
ZhuXWangSYuL, et al.HDAC3 Negatively regulates spatial memory in a mouse model of Alzheimer's disease. Aging Cell2017; 16: 1073–1082.
17.
RumbaughGDawsSEOzkanED, et al.Pharmacological selectivity within class I histone deacetylases predicts effects on synaptic function and memory rescue. Neuropsychopharmacology2015; 40: 2307–2316.
18.
CohenRMRezai-ZadehKWeitzTM, et al.A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J Neurosci2013; 33: 6245–6256.
19.
SaréRMCookeSKKrychL, et al.Behavioral phenotype in the TgF344-AD rat model of Alzheimer's disease. Front Neurosci2020; 14: 601.
20.
RodriguezSHugCTodorovP, et al.Machine learning identifies candidates for drug repurposing in Alzheimer's disease. Nat Commun2021; 12: 1033.
21.
HodesRJBuckholtzN. Accelerating medicines partnership: Alzheimer's Disease (AMP-AD) knowledge portal aids Alzheimer's drug discovery through open data sharing. Expert Opin Ther Targets2016; 20: 389–391.
22.
LimHPoleksicAYaoY, et al.Large-scale off-target identification using fast and accurate dual regularized one-class collaborative filtering and its application to drug repurposing. PLoS Comput Biol2016; 12: e1005135.
23.
JohnstonTHHuotPDamudeS, et al.RGFP109, A histone deacetylase inhibitor attenuates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset: a proof-of-concept study. Parkinsonism Relat Disord2013; 19: 260–264.
24.
RaiMSoragniEChouCJ, et al.Two new pimelic diphenylamide HDAC inhibitors induce sustained frataxin upregulation in cells from friedreich's ataxia patients and in a mouse model. PLoS One2010; 5: e8825.
25.
SandiCPintoRMAl-MahdawiS, et al.Prolonged treatment with pimelic o-aminobenzamide HDAC inhibitors ameliorates the disease phenotype of a Friedreich ataxia mouse model. Neurobiol Dis2011; 42: 496–505.
26.
SperlingRMorminoEJohnsonK. The evolution of preclinical Alzheimer's disease: implications for prevention trials. Neuron2014; 84: 608–622.
27.
LesburguèresESparksFTO'ReillyKCet al.Active place avoidance is no more stressful than unreinforced exploration of a familiar environment. Hippocampus2016; 26: 1481–1485.
28.
RajanKBWilsonRSWeuveJ, et al.Cognitive impairment 18 years before clinical diagnosis of Alzheimer disease dementia. Neurology2015; 85: 898–904.
29.
PicciniCPecoriDCampaniD, et al.Alzheimer's disease: patterns of cognitive impairment at different levels of disease severity. J Neurol Sci1998; 156: 59–64.
30.
Cronin-GolombACorkinSRizzoJF, et al.Visual dysfunction in Alzheimer's disease: relation to normal aging. Ann Neurol1991; 29: 41–52.
31.
SchmidtkeKOlbrichS. The clock Reading test: validation of an instrument for the diagnosis of dementia and disorders of visuo-spatial cognition. Int Psychogeriatr2007; 19: 307–321.
32.
HopeTKeeneJMcShaneRH, et al.Wandering in dementia: a longitudinal study. Int Psychogeriatr2001; 13: 137–147.
33.
RaoYLGanarajaBMurlimanjuBV, et al.Hippocampus and its involvement in Alzheimer's disease: a review. 3 Biotech2022; 12: 55.
34.
AllenGBarnardHMcCollR, et al.Reduced hippocampal functional connectivity in Alzheimer disease. Arch Neurol2007; 64: 1482–1487.
35.
SimicGKostovicIWinbladB, et al.Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer's disease. J Comp Neurol1997; 379: 482–494.
36.
KrilJJHodgesJHallidayG. Relationship between hippocampal volume and CA1 neuron loss in brains of humans with and without Alzheimer's disease. Neurosci Lett2004; 361: 9–12.
37.
WallaceCHOliverosGSerranoPA, et al.Timapiprant, a prostaglandin D2 receptor antagonist, ameliorates pathology in a rat Alzheimer's model. Life Sci Alliance2022; 5: e202201555.
38.
SilvaAMartínezMC. Spatial memory deficits in Alzheimer's disease and their connection to cognitive maps’ formation by place cells and grid cells. Front Behav Neurosci2022; 16: 1082158.
39.
TeamRC. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, https://www.R-project.org/ (2021), accessed 6 December 2023.
40.
PaxinosGWatsonC. The rat brain in stereotaxic coordinates. 7th ed. New York: Academic Press, 2013.
ChenSWangCEberlyLE, et al.Adaptive control of the false discovery rate in voxel-based morphometry. Hum Brain Mapp2009; 30: 2304–2311.
43.
KarperienAAhammerHJelinekHF. Quantitating the subtleties of microglial morphology with fractal analysis. Front Cell Neurosci2013; 7: 3.
44.
ZussoMMethotLLoR, et al.Regulation of postnatal forebrain amoeboid microglial cell proliferation and development by the transcription factor Runx1. J Neurosci2012; 32: 11285–11298.
45.
JooILLaiAYBazzigaluppiP, et al.Early neurovascular dysfunction in a transgenic rat model of Alzheimer's disease. Sci Rep2017; 7: 46427.
46.
CimadevillaJMFentonAABuresJ. New spatial cognition tests for mice: passive place avoidance on stable and active place avoidance on rotating arenas. Brain Res Bull2001; 54: 559–563.
47.
DudaWWęsierskaM. Spatial working memory in rats: crucial role of the hippocampus in the allothetic place avoidance alternation task demanding stimuli segregation. Behav Brain Res2021; 412: 113414.
48.
KalováEVlcekKJarolímováE, et al.Allothetic orientation and sequential ordering of places is impaired in early stages of Alzheimer's disease: corresponding results in real space tests and computer tests. Behav Brain Res2005; 159: 175–186.
49.
NedelskaZAndelRLaczóJ, et al.Spatial navigation impairment is proportional to right hippocampal volume. Proc Natl Acad Sci U S A2012; 109: 2590–2594.
50.
BerkowitzLEHarveyREDrakeE, et al.Progressive impairment of directional and spatially precise trajectories by TgF344-Alzheimer's disease rats in the Morris Water Task. Sci Rep2018; 8: 16153.
51.
BernaudVEBulenHLPeñaVL, et al.Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer’s disease: three key timepoints through middle-age in females. Sci Rep2022; 12: 14596.
52.
ChaudryONdukweKXieL, et al.Females exhibit higher GluA2 levels and outperform males in active place avoidance despite increased amyloid plaques in TgF344-Alzheimer’s rats. Sci Rep2022; 12: 19129.
53.
SebastianVVergelTBaigR, et al.PKMzeta differentially utilized between sexes for remote long-term spatial memory. PLoS One2013; 8: e81121.
54.
MiguesPVHardtOWuDC, et al.PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nat Neurosci2010; 13: 630–634.
55.
VourosAGehringTVSzydlowskaK, et al.A generalised framework for detailed classification of swimming paths inside the Morris Water Maze. Sci Rep2018; 8: 15089.
56.
VourosAGehringTVJuraB, et al.Strategies discovery in the active allothetic place avoidance task. Sci Rep2022; 12: 12675.
57.
JanczuraKJVolmarCHSartorGC, et al.Inhibition of HDAC3 reverses Alzheimer's disease-related pathologies in vitro and in the 3xTg-AD mouse model. Proc Natl Acad Sci U S A2018; 115: E11148–e11157.
58.
KilgoreMMillerCAFassDM, et al.Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology2010; 35: 870–880.
59.
ShivakumarMSubbannaSJoshiV, et al.Postnatal ethanol exposure activates HDAC-mediated histone deacetylation, impairs synaptic plasticity gene expression and behavior in mice. Int J Neuropsychopharmacol2020; 23: 324–338.
60.
GuanJSHaggartySJGiacomettiE, et al.HDAC2 Negatively regulates memory formation and synaptic plasticity. Nature2009; 459: 55–60.
61.
BredyTWWuHCregoC, et al.Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem2007; 14: 268–276.
62.
McQuownSCBarrettRMMatheosDP, et al.HDAC3 Is a critical negative regulator of long-term memory formation. J Neurosci2011; 31: 764–774.
63.
RumbaughGSillivanSEOzkanED, et al.Pharmacological selectivity within class I histone deacetylases predicts effects on synaptic function and memory rescue. Neuropsychopharmacology2015; 40: 2307–2316.
64.
IntlekoferKABerchtoldNCMalvaezM, et al.Exercise and sodium butyrate transform a subthreshold learning event into long-term memory via a brain-derived neurotrophic factor-dependent mechanism. Neuropsychopharmacology2013; 38: 2027–2034.
65.
SinghPKonarAKumarA, et al.Hippocampal chromatin-modifying enzymes are pivotal for scopolamine-induced synaptic plasticity gene expression changes and memory impairment. J Neurochem2015; 134: 642–651.
66.
GräffJWoldemichaelBTBerchtoldD, et al.Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation. Nat Commun2012; 3: 991.
67.
GalloFTKatcheCMoriciJF, et al.Immediate early genes, memory and psychiatric disorders: focus on c-Fos, Egr1 and Arc. Front Behav Neurosci2018; 12: 79.
68.
YagiSDrewczynskiDWainwrightSR, et al.Sex and estrous cycle differences in immediate early gene activation in the hippocampus and the dorsal striatum after the cue competition task. Horm Behav2017; 87: 69–79.
69.
FortressAMKimJPooleRL, et al.17β-Estradiol Regulates histone alterations associated with memory consolidation and increases Bdnf promoter acetylation in middle-aged female mice. Learn Mem2014; 21: 457–467.
70.
HeldtSAStanekLChhatwalJP, et al.Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry2007; 12: 656–670.
71.
YouDRichardsonJRAleksunesLM. Epigenetic regulation of multidrug resistance protein 1 and breast cancer resistance protein transporters by histone deacetylase inhibition. Drug Metab Dispos2020; 48: 459–480.
72.
ParkHJKimMJRothenbergerC, et al.GSTA4 Mediates reduction of cisplatin ototoxicity in female mice. Nat Commun2019; 10: 4150.
73.
Lopes-RamosCMKuijjerMLOginoS, et al.Gene regulatory network analysis identifies sex-linked differences in colon cancer drug metabolism. Cancer Res2018; 78: 5538–5547.
74.
KnightTRChoudhuriSKlaassenCD. Constitutive mRNA expression of various glutathione S-transferase isoforms in different tissues of mice. Toxicol Sci2007; 100: 513–524.
75.
WangLZRamírezJYeoW, et al.Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients. PLoS One2013; 8: e54522.
76.
BallietRMChenGGallagherCJ, et al.Characterization of UGTs active against SAHA and association between SAHA glucuronidation activity phenotype with UGT genotype. Cancer Res2009; 69: 2981–2989.
77.
DongDZhangTLuD, et al.In vitro characterization of belinostat glucuronidation: demonstration of both UGT1A1 and UGT2B7 as the main contributing isozymes. Xenobiotica2017; 47: 277–283.
78.
RaftogianisRCrevelingCWeinshilboumR, et al.Estrogen metabolism by conjugation. J Natl Cancer Inst Monogr2000; 27: 113–124.
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