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Translational Neurodegeneration
Published in: Translational Neurodegeneration 1/2017

Open Access 01-12-2017 | Review

The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer’s disease

Authors: Shuang-shuang Yang, Rui Zhang, Gang Wang, Yong-fang Zhang

Published in: Translational Neurodegeneration | Issue 1/2017

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Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, which is associated with learning and memory impairment in the elderly. Recent studies have found that treating AD in the way of chromatin remodeling via histone acetylation is a promising therapeutic regimen. In a number of recent studies, inhibitors of histone deacetylase (HDACs) have been found to be a novel promising therapeutic agents for neurological disorders, particularly for AD and other neurodegenerative diseases. Although HDAC inhibitors have the ability to ameliorate cognitive impairment, successful treatments in the classic AD animal model are rarely translated into clinical trials. As for the reduction of unwanted side effects, the development of HDAC inhibitors with increased isoform selectivity or seeking other directions is a key issue that needs to be addressed. The review focused on literatures on epigenetic mechanisms in recent years, especially on histone acetylation in terms of the enhancement of specificity, efficacy and avoiding side effects for treating AD.
Literature
1.
Xu K, Dai XL, Huang HC, Jiang ZF. Targeting HDACs: a promising therapy for Alzheimer's disease. Oxidative Med Cell Longev. 2011;2011:143269.CrossRef
2.
Zuo L, Hemmelgarn BT, Chuang CC, Best TM. The role of Oxidative stress-induced epigenetic alterations in Amyloid-beta production in Alzheimer's disease. Oxidative Med Cell Longev. 2015;2015:604658.CrossRef
3.
Li X, Bao X, Wang R. Neurogenesis-based epigenetic therapeutics for Alzheimer's disease (review). Mol Med Rep. 2016;14(2):1043–53.PubMed
4.
Liu RT, Zou LB, Lu QJ. Liquiritigenin inhibits Abeta(25-35)-induced neurotoxicity and secretion of Abeta(1-40) in rat hippocampal neurons. Acta Pharmacol Sin. 2009;30(7):899–906.CrossRefPubMedPubMedCentral
5.
Fischer A. Targeting histone-modifications in Alzheimer's disease. What is the evidence that this is a promising therapeutic avenue? Neuropharmacology. 2014;80:95–102.CrossRefPubMed
6.
Konsoula Z, Barile FA. Epigenetic histone acetylation and deacetylation mechanisms in experimental models of neurodegenerative disorders. J Pharmacol Toxicol Methods. 2012;66(3):215–20.CrossRefPubMed
7.
Mai A, Rotili D, Valente S, Kazantsev AG. Histone deacetylase inhibitors and neurodegenerative disorders: holding the promise. Curr Pharm Des. 2009;15(34):3940–57.CrossRefPubMed
8.
Song JM, Sung YM, Nam JH, Yoon H, Chung A, Moffat E, Jung M, Pak DTS, Kim J, Hoe HS. A Mercaptoacetamide-based class II Histone Deacetylase inhibitor increases Dendritic spine density via RasGRF1/ERK pathway. J Alzheimers Dis. 2016;51(2):591–604.CrossRefPubMed
9.
Benito E, Urbanke H, Ramachandran B, Barth J, Halder R, Awasthi A, Jain G, Capece V, Burkhardt S, Navarro-Sala M, et al. HDAC inhibitor-dependent transcriptome and memory reinstatement in cognitive decline models. J Clin Invest. 2015;125(9):3572–84.CrossRefPubMedPubMedCentral
10.
Graeff J, Tsai L-H: The potential of HDAC inhibitors as cognitive enhancers. In: Annual review of pharmacology and toxicology, Vol 53, 2013. Volume 53, edn. Edited by Insel PA; 2013: 311-330.
11.
Hahnen E, Hauke J, Trankle C, Eyupoglu IY, Wirth B, Blumcke I. Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opin Investig Drugs. 2008;17(2):169–84.CrossRefPubMed
12.
Lockett GA, Wilkes F, Maleszka R. Brain plasticity, memory and neurological disorders: an epigenetic perspective. Neuroreport. 2010;21(14):909–13.CrossRefPubMed
13.
Kerridge C, Belyaev ND, Nalivaeva NN, Turner AJ. The a beta-clearance protein transthyretin, like neprilysin, is epigenetically regulated by the amyloid precursor protein intracellular domain. J Neurochem. 2014;130(3):419–31.CrossRefPubMed
14.
Zhang ZY, Schluesener HJ. Oral administration of histone deacetylase inhibitor MS-275 ameliorates neuroinflammation and cerebral amyloidosis and improves behavior in a mouse model. J Neuropathol Exp Neurol. 2013;72(3):178–85.CrossRefPubMed
15.
Lu X, Wang L, Yu CJ, Yu DH, Yu G. Histone acetylation modifiers in the pathogenesis of Alzheimer's disease. Front Cell Neurosci. 2015;9:3.CrossRef
16.
Rumbaugh G, Sillivan SE, Ozkan ED, Rojas CS, Hubbs CR, Aceti M, Kilgore M, Kudugunti S, Puthanveettil SV, Sweatt JD, et al. Pharmacological selectivity within class I Histone Deacetylases predicts effects on synaptic function and memory rescue. Neuropsychopharmacology. 2015;40(10):2307–16.CrossRefPubMedPubMedCentral
17.
Sung YM, Lee T, Yoon H, DiBattista AM, Song JM, Sohn Y, Moffat EI, Turner RS, Jung M, Kim J, et al. Mercaptoacetamide-based class II HDAC inhibitor lowers Abeta levels and improves learning and memory in a mouse model of Alzheimer's disease. Exp Neurol. 2013;239:192–201.CrossRefPubMed
18.
Krishna K, Behnisch T, Sajikumar S. Inhibition of Histone Deacetylase 3 restores Amyloid-beta Oligomer-induced plasticity deficit in Hippocampal CA1 pyramidal neurons. J Alzheimers Dis. 2016;51(3):783–91.CrossRefPubMed
19.
Agis-Balboa RC, Pavelka Z, Kerimoglu C, Fischer A. Loss of HDAC5 impairs memory function: implications for Alzheimer's disease. J Alzheimers Dis. 2013;33(1):35–44.PubMed
20.
Zhang L, Liu C, Wu J, Tao JJ, Sui XL, Yao ZG, Xu YF, Huang L, Zhu H, Sheng SL, et al. Tubastatin a/ACY-1215 improves cognition in Alzheimer's disease transgenic mice. J Alzheimer's Dis. 2014;41(4):1193–205.
21.
Cook C, Gendron TF, Scheffel K, Carlomagno Y, Dunmore J, DeTure M, Petrucelli L. Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation. Hum Mol Genet. 2012;21(13):2936–45.CrossRefPubMedPubMedCentral
22.
Kim C, Choi H, Jung ES, Lee W, Oh S, Jeon NL, Mook-Jung I. HDAC6 inhibitor blocks Amyloid Beta-induced impairment of mitochondrial transport in Hippocampal neurons. PLoS One. 2012:7(8).
23.
Robers MB, Dart ML, Woodroofe CC, Zimprich CA, Kirkland TA, Machleidt T, Kupcho KR, Levin S, Hartnett JR, Zimmerman K, et al. Target engagement and drug residence time can be observed in living cells with BRET. Nat Commun. 2015;6:10091.CrossRefPubMedPubMedCentral
24.
Govindarajan N, Rao P, Burkhardt S, Sananbenesi F, Schluter OM, Bradke F, Lu J, Fischer A. Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease. EMBO Mol Med. 2013;5(1):52–63.CrossRefPubMed
25.
Zhang L, Liu C, Wu J, Tao J-J, Sui X-L, Yao Z-G, Xu Y-F, Huang L, Zhu H, Sheng S-L, et al. Tubastatin a/ACY-1215 improves cognition in Alzheimer's disease transgenic mice. J Alzheimers Dis. 2014;41(4):1193–205.PubMed
26.
Cook C, Carlomagno Y, Gendron TF, Dunmore J, Scheffel K, Stetler C, Davis M, Dickson D, Jarpe M, DeTure M, et al. Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance. Hum Mol Genet. 2014;23(1):104–16.CrossRefPubMed
27.
Lehar J, Krueger AS, Avery W, Heilbut AM, Johansen LM, Price ER, Rickles RJ, Short GF 3rd, Staunton JE, Jin X, et al. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat Biotechnol. 2009;27(7):659–66.CrossRefPubMedPubMedCentral
28.
29.
Cuadrado-Tejedor M, Garcia-Barroso C, Sanzhez-Arias J, Mederos S, Rabal O, Ugarte A, Franco R, Pascual-Lucas M, Segura V, Perea G, et al. Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer's disease. Clin Epigenetics. 2015;7.
30.
Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology. 2010;35(4):870–80.CrossRefPubMed
31.
Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007;26(37):5541–52.CrossRefPubMed
32.
Meng J, Li Y, Camarillo C, Yao Y, Zhang Y, Xu C, Jiang L. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity. PLoS One. 2014;9(1):e85570.CrossRefPubMedPubMedCentral
33.
Cuadrado-Tejedor M, Oyarzabal J, Lucas MP, Franco R, Garcia-Osta A. Epigenetic drugs in Alzheimer's disease. Biomol concepts. 2013;4(5):433–45.CrossRefPubMed
34.
Cuadrado-Tejedor M, Garcia-Barroso C, Sánchez-Arias JA, Rabal O, Pérez-González M, Mederos S, Ugarte A, Franco R, Segura V, Perea G, et al. A first-in-class small-molecule that acts as a dual inhibitor of HDAC and PDE5 and that rescues Hippocampal synaptic impairment in Alzheimer's disease mice. Neuropsychopharmacology. 2017;42(2):524–39.CrossRefPubMed
35.
Yao Z-G, Liu Y, Zhang L, Huang L, Ma C-M, Xu Y-F, Zhu H, Qin C. Co-location of HDAC2 and insulin signaling components in the adult mouse hippocampus. Cell Mol Neurobiol. 2012;32(8):1337–42.CrossRefPubMed
36.
Noh H, Seo H. Age-dependent effects of valproic acid in Alzheimer's disease (AD) mice are associated with nerve grow factor (NGF) regulation. Neuroscience. 2014;266:255–65.CrossRefPubMed
37.
Liu H, Zhang JJ, Li X, Yang Y, Xie XF, Hu K. Post-occlusion administration of sodium butyrate attenuates cognitive impairment in a rat model of chronic cerebral hypoperfusion. Pharmacol Biochem Behav. 2015;135:53–9.CrossRefPubMed
38.
Graff J, Tsai LH. The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol. 2013;53:311–30.CrossRefPubMed
39.
Zhan P, Wang X, Liu X, Suzuki T. Medicinal chemistry insights into novel HDAC inhibitors: an updated patent review (2012-2016). Recent Pat Anticancer Drug Discov. 2017;12(4):16–34.
Metadata
Title
The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer’s disease
Authors
Shuang-shuang Yang
Rui Zhang
Gang Wang
Yong-fang Zhang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Translational Neurodegeneration / Issue 1/2017
Electronic ISSN: 2047-9158
DOI
https://doi.org/10.1186/s40035-017-0089-1

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