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
- M. Cuadrado-Tejedor†1, 6,
- C. Garcia-Barroso†1,
- J. Sanzhez-Arias2,
- S. Mederos3,
- O. Rabal2,
- A. Ugarte2,
- R. Franco1, 4,
- M. Pascual-Lucas1,
- V. Segura5,
- G. Perea3,
- J. Oyarzabal†2Email author and
- A. Garcia-Osta†1Email author
© Cuadrado-Tejedor et al. 2015
Received: 5 May 2015
Accepted: 28 September 2015
Published: 8 October 2015
Given the implication of histone acetylation in memory processes, histone deacetylase inhibitors (HDACIs) have been postulated as potential modulators of cognitive impairment in Alzheimer’s disease (AD). However, dose-dependent side effects have been described in patients with the currently available broad-spectrum HDACIs, explaining why their therapeutic potential has not been realized for chronic diseases. Here, by simultaneously targeting two independent enzyme activities, histone deacetylase (HDAC) and phosphodiesterase-5 (PDE5), we propose a novel mode of inhibitory action that might increase the therapeutic specificity of HDACIs.
The combination of vorinostat, a pan-HDACI, and tadalafil, a PDE5 inhibitor, rescued the long-term potentiation impaired in slices from APP/PS1 mice. When administered in vivo, the combination of these drugs alleviated the cognitive deficits in AD mice, as well as the amyloid and tau pathology, and it reversed the reduced dendritic spine density on hippocampal neurons. Significantly, the combination of vorinostat and tadalafil was more effective than each drug alone, both against the symptoms and in terms of disease modification, and importantly, these effects persisted after a 4-week washout period.
The results highlight the pharmacological potential of a combination of molecules that inhibit HDAC and PDE5 as a therapeutic approach for AD treatment.
KeywordsHistone deacetylase (HDAC) Phosphodiesterase (PDE) Alzheimer’s disease (AD) Memory Amyloid Tau Gene transcription
There is now considerable evidence that epigenetic regulation is a dynamic and critical mechanism modulating neuronal function. It was recently suggested that memory impairment in Alzheimer’s disease (AD) is caused by a “reversible” epigenetic blockade of gene transcription . One epigenetic mechanism that regulates gene transcription is histone acetylation, a modification that is known to enhance or constrain cognitive functions. In fact, from a therapeutic point of view, histone deacetylase inhibitors (HDACIs) have emerged as promising compounds that might help manage AD. However, the toxicity associated with HDACIs has limited the clinical data available, a phenomenon that may have an important impact in patients receiving long-term therapy . In order to reduce side effects while maintaining cognitive benefits, one strategy would be to develop isoform-selective HDACIs. However, since the side effects reported for HDACIs in humans are dose dependent , the use of lower doses of pan-HDAC inhibitors to reduce their toxicity could represent another solution, combining them with other AD-related drugs to obtain a compound or synergistic effect.
Targeting multiple elements in the network underlying AD may produce benefits beyond those of representative monotherapies. Accordingly, for the first time, we propose here a new therapeutic approach to treat AD that targets two independent but synergistic pathways related to different aspects of the disease. Specifically, we propose combining the inhibition of HDACs with that of phosphodiesterase-5 (PDE5), an enzyme that targets another intracellular pathway involved in memory formation and other AD-related features [4–6]. PDE5 inhibitors regulate signalling pathways by elevating cGMP, and they may ultimately promote gene transcription by directly and/or indirectly activating binding to the cAMP response element (CREB) . CREB plays an essential role in regulating the transcription of genes involved in the consolidation of long-term memories [8, 9]. Moreover, its interaction with the CREB-binding protein (CBP) improves memory and enhances synaptic plasticity through HDAC inhibition . Hence, the activation of CREB would be expected to further potentiate the enhancement of memory and synaptic plasticity induced by HDACIs . In line with this idea, PDE5 inhibitors could drive the gene transcription induced by histone acetylation to favour that of CREB-dependent memory-related genes, avoiding global transcriptional activation. Likewise, and due to “epigenetic priming” , HDACIs may sensitize the cell’s response to PDE5 inhibitors, facilitating the transcription of CREB-dependent genes and thereby improving therapeutic selectivity.
To assess the potential therapeutic value of concomitant HDAC and PDE5 inhibition in AD, we used the HDACI vorinostat and the PDE5 inhibitor tadalafil as reference compounds. A synergism between these two inhibitors when co-administered at sub-effective doses was not only achieved in terms of memory function but also in reducing the amyloid pathology. Thus, the concomitant inhibition of HDAC and PDE5 may represent a novel symptomatic and disease-modifying strategy to treat AD.
The concomitant inhibition of HDAC and PDE5 has a synergistic effect on histone acetylation
Concomitant inhibition of HDAC and PDE5 had a synergistic effect on long-term potentiation in APP/PS1 transgenic mice
The effects of vorinostat and tadalafil combination therapy on memory function in aged Tg2576 mice
A 2–3-week treatment with vorinostat (50 mg/kg) restored contextual memory deficits in the APPswe/PS1dE9 AD mouse model , and likewise, tadalafil (15 mg/kg) improves memory deficits in an aged AD mouse model . Thus, we tested whether the combined administration of lower doses of both of these compounds could restore cognitive deficits in the Tg2576 AD mouse model. To test this hypothesis, we treated 14–16-month-old Tg2576 mice for 4 weeks with tadalafil (1 mg/kg, p.o.) and vorinostat (12.5 mg/kg, i.p.), with either inhibitor alone (tadalafil [1 mg/kg, p.o.] or vorinostat [12.5 mg/kg, i.p.]), or with the vehicle alone (10 % DMSO) daily. We performed an initial pharmacokinetic study of the administration of vorinostat, tadalafil or combined vorinostat and tadalafil at these doses in plasma and brain samples. The brain/plasma ratios 20 min after combined vorinostat and tadalafil administration were 11 % for tadalafil and 5.5 % for vorinostat, corresponding to brain concentrations of 30 and 345.5 nmol/kg (Additional file 1: Figure S1 and Table S1).
Finally, the drug treatments were followed by a washout period of 4 weeks, after which mice were re-trained in a reversal phase of the MWM test, placing the platform in the opposite quadrant. The hidden platform training was carried out over 5 days (four trials per day) and followed by a memory retention probe test on day 6. Tg2576 mice treated with the vehicle performed worse than WT mice in both the acquisition (F(1, 28) = 7.0, p ≤ 0.01: Additional file 1: Figure S2e) and the retention phase on day 6 (t(29) = 2.8, p ≤ 0.01: Additional file 1: Figure S2f). By contrast, these transgenic mice treated with the combination therapy displayed a significantly shorter escape latency than the control Tg2576 mice that received the vehicle alone (F(3,196) = 10.5, p ≤ 0.001: Fig. 3e). Once again, the animals that received vorinostat alone also showed lower escape latencies than the Tg2576 mice that receive the vehicle alone (F(3,196) = 10.5, p ≤ 0.05: Fig. 3e). During the probe test, only the group of animals receiving the combination of vorinostat and tadalafil spent significantly more time in the target quadrant compared with the vehicle-treated mice (F(3,36) = 4.0, p ≤ 0.05: Fig. 3f). Together, these results indicate that combination therapy of vorinostat and tadalafil during 4 weeks restored memory impairment in aged Tg2576 mice whose cognition was severely affected. Furthermore, this effect was maintained after a 4-week washout period. Interestingly, the treatment with vorinostat enhances the learning capacity of transgenic mice, yet memory was not consolidated by this drug alone since no differences were detected between Tg2676 mice receiving the vehicle alone or vorinostat during the probe tests.
Effects of vorinostat and tadalafil combination therapy on pathological AD markers in aged Tg2576 mice
We also tested whether the behavioural recovery induced by the combination therapy reflected structural changes, such as the density of dendritic spines. The density of spines on hippocampal CA1 pyramidal neurons was analyzed in Tg2576 mice and their WT littermates using an optimized Golgi impregnation method. In line with previous findings , a significantly lower density of apical dendrites was found on CA1 pyramidal neurons in Tg2576 mice than in WT mice (t(70) = 3.9, p ≤ 0.001: Additional file 1: Figure S3b), while treatment with tadalafil, vorinostat or the combination of these drugs reversed the deficit in spine density on apical CA1 dendrites, which returned to control values (F(3,141) = 12.6, p ≤ 0.001: Fig. 4e). These results suggest that the reduction in spine density is reversible even long after disease onset, which might account for the memory improvement observed and maintained for 4 weeks after washout. However, other mechanisms may influence memory recovery since the effect on dendritic spine density in the mice that receive tadalafil alone was not correlated with the behavioural data.
Gene expression induced by vorinostat, tadalafil and the combination of the two in the hippocampus of Tg2576 mice
There is convincing evidence that HDACs represent suitable drug targets for therapeutic intervention of AD [16, 20, 21]. However, their adverse side effects mean they are not an option for chronic treatments . While the administration of selective HDACIs represents an attractive potential solution to this challenge , counteracting their off-target effects may require sacrificing some of the beneficial effects obtained with current broad-spectrum HDACIs. However, the use of low doses of pan-HDACIs in combination therapy could reduce toxic side effects and might synergistically enhance efficacy. Here, we demonstrate that the co-administration of sub-effective doses of tadalafil, a safe and well-tolerated specific PDE5 inhibitor, together with the HDACI, vorinostat, produces a synergistic effect that prevents the disruption in synaptic plasticity displayed in AD mice. The amelioration in memory impairment exhibited by the treated Tg2576 mice was accompanied by a significant reduction in amyloid and tau pathologies, and the recovery of dendritic spines. Indeed, this combination therapy induces a distinct transcriptional profile in the hippocampus of transgenic mice that may underlie the restoration of the AD phenotype.
Chromatin remodelling due to changes in histone acetylation induces the transcription of genes that encode proteins involved in the growth of new synapses and the increase in synaptic strength [24, 25]. The enhancement of hippocampus-dependent memories by HDACIs required CREB and its interaction with CBP . Indeed, a novel HDACI, crebinostat, enhances memory in mice by facilitating CREB-dependent transcription . Here, we demonstrate a synergistic effect of vorinostat and tadalafil in the induction of the epigenetic response (AcH3K9 levels), suggesting that both the pathways affected by these inhibitors may interact at some point. By elevating cGMP levels, PDE5 inhibition may also produce CREB activation and the recruitment of CBP, a histone acetyltransferase capable of altering chromatin structure . This mechanism could be responsible for restoring LTP and enhancing memory, as observed when the combination of vorinostat and tadalafil was administered to AD transgenic mice. Moreover, the fact that the reversion of memory deficits and synapse loss in aged Tg2576 mice was maintained even after a washout period of 4 weeks suggests that targeting HDAC and PDE5 simultaneously triggers long-lasting changes in plastic remodelling that may be particularly interesting to counteract memory decline in AD.
GSEA data show that the pathways associated with synaptic plasticity are affected by combined treatment with vorinostat and tadalafil and that these effects may be responsible for enhancing memory in Tg2576 mice by augmenting the expression of genes involved in synaptic transmission. The restoration of LTP in APP/PS1 slice mice administered these two inhibitors supports this hypothesis. Interestingly, using a theoretical-biological model that simulates the induction of LTP and of Rubinstein-Taybi syndrome (RTS)-induced LTP deficits, it was predicted that the combination of HDAC and PDE inhibitors would rescue LTP deficits in the RST model . Our results verify the beneficial synergistic effects predicted by this theoretical model.
With regard to AD markers, a reduction in tau pathology was observed in all the mice that received the inhibitors, alone or in combination. Indeed, PDE5 inhibition through the regulation of the Akt/GSK3β pathway is believed to decrease pTau levels [17, 28]. Moreover, the activity of vorinostat on HDAC6 (IC50 10 nM) increases α-tubulin acetylation, possibly one of the mechanisms involved in the amelioration of the tau pathology [29, 30]. Evidence is accumulating that α-tubulin acetylation plays a critical role in the clearance of misfolded and aggregated proteins, since it has been shown to influence aggresome formation as a means of cell protection [31, 32]. Thus, the inhibitory effect of vorinostat on HDAC6 is also likely to participate in the amelioration of amyloid pathology observed with the combination therapy [33, 34]. Nevertheless, a synergistic effect on the transcription of genes involved in amyloid production and/or clearance should also be considered since no effect was observed in the mice that receive vorinostat alone (pan-HDAC inhibitor). Thus, further studies will be necessary to explore the mechanisms involved in the reduction of amyloid and tau pathologies.In summary, the concomitant inhibition of HDAC and PDE5 shown in this study may reverse AD-related pathology through different mechanism of action, some of which remain to be explored (Fig. 5).
In summary, we propose a new therapeutic approach with potential to treat AD that simultaneously targets HDAC and PDE5. This synergism may make it possible to achieve more optimal safety profiles for HDACIs, making them suitable for chronic treatments. On the one hand, this study suggests that potent HDAC inhibition is not necessary to obtain an efficacious functional response (H3K9 acetylation), and on the other hand, if the changes induced in gene expression underlie the recovery of memory, then simply activating specific gene programmes might be sufficient. Accordingly, molecules with a short half-life and residence time might even produce optimal therapeutic effects. Hence, this may just be the starting point to design and identify molecules with adequate dual activity and that are both efficacious and safe. Moreover, the data presented validate the use of a systems therapeutics approach to drug discovery.
For in vitro studies, tadalafil (Euroasian Chemicals Private Ltd., Mumbai, India) and vorinostat (Cayman Chemical Company, Ann Arbor, MI, USA) were dissolved in DMSO at 10 mM and to final concentrations in medium cell. For in vivo studies, tadalafil (Cialis, Eli Lilly & Company) was administered in vivo by oral gavage at a dose of 1 mg/kg and was prepared as previously described . Vorinostat was administered intraperitoneally (i.p.) at a dose of 12.5 mg/kg and was dissolved in 10 % DMSO, 10 % Tween-20 and 90 % saline solution.
Primary neuronal cultures and treatments
Primary neuronal cultures were obtained from the hippocampus of embryonic day 16 (E16) wild-type (WT) mice and used at 15 days in vitro (DIV) . Cultures were treated for 2 h with tadalafil, vorinostat or the combination of vorinostat and tadalafil at different concentrations during 2 h. For Western blot analysis, hippocampal neurons were collected after the different treatments in a cold lysis buffer with protease inhibitors .
Acetyl-Histone H3 Lysine 9 (H3K9ac) cellular detection assay (AlphaLisa technology)
Briefly, 2000 cells (SH-SY5Y) were plated in a poly-d-lysine-treated 384-well plate. Cells were incubated with different concentrations of vorinostat and tadalafil during 2 h. After incubation, the medium was removed and cells were lysed, histones were extracted and histone carrying the acetylation mark was detected following the manufacturer’s instructions (PerkinElmer; Cat number AL714 A/C kit assay). Signal of acetylation mark was obtained after 18 h of dark incubation at room temperature and was normalized by the unmodified histone signal and calculated as folds over basal levels, considered as those obtained in the absence of assayed compounds.
Hippocampal slices from APP/PS1 mice, positive and WT littermate mice (6–9 months) were stimulated with bipolar electrodes and recorded with a glass microelectrode placed on the stratum radiatum of the hippocampal CA1 region to monitor extracellular postsynaptic field potentials (fPSPs). Baseline responses were recorded and test stimuli given at 0.1 Hz. Slope of fPSP was analyzed before and after high-frequency stimulation protocol. See the Additional file 1: Additional methods for further details.
Animals and chronic treatments
Transgenic mice (Tg2576) overexpressing human amyloid precursor protein (hAPP) carrying the Swedish (K670N/M671L) familial AD mutation under control of the prion promoter  were used. Mice were on an inbred C57BL/6/SJL genetic background. Animals were housed four to five per cage with free access to food and water, and maintained in a temperature-controlled environment on a 12-h light-dark cycle. Tg2576 female mice (14–16 months old) were treated once daily with tadalafil (1 mg/kg, p.o.), vorinostat (12.5 mg/kg, i.p.), tadalafil (1 mg/kg, p.o.) + vorinostat (12.5 mg/kg, i.p.) (this treatment will be defined as combination therapy), or vehicle for 4 weeks. Behavioural and biochemical studies were performed comparing transgenic mice to age- and strain-matched transgenic negative littermates (WT).
Behavioural studies were carried out during light time (from 9 a.m. to 2 p.m.). Protocols were approved by the Ethical Committee of the University of Navarra (in accordance with the European and Spanish Royal Decree 1201/2005).
Fear conditioning test (FC)
To evaluate the effects of drugs on cognitive function after 2 weeks of treatment, fear conditioning paradigm was used as described in . Freezing scores were expressed as percentages. The conditioning procedure was carried out in a StartFear system (Panlab S.L., Barcelona, Spain).
Morris water maze test (MWM)
After 3 weeks of treatment, we used the MWM test to evaluate the working and reference memory function in Tg2576 mice, as previously described . In addition, after a 4-week washout period of the drugs, a reversal phase of MWM was carried out. In this phase, the platform was placed in the opposite quadrant of the tank, and the hidden platform training during five consecutive days (four trials per day) was performed. All cues remained in their original positions. Memory retention was analyzed in a probe at day 6. All experimental procedures were performed blind to groups. Animals were euthanized 24 h after the last probe. One hippocampus of three animals per group (vehicle, vorinostat, tadalafil and the combination) was used for RNA extraction, Affymetrix microarray hybridization and data analysis (see Additional file 1: Additional methods).
Determination of Aβ levels
Parieto-temporal cortical Aβ42 levels were measured by using a sensitive sandwich ELISA kit (Invitrogen, Camarillo, CA). We measured Aβ42 pool containing intracellular and membrane-associated Aβ42 that may be more closely related to the expression of AD signs than other measured Aβ42 species . The tissue was homogenized in a buffer containing SDS 2 %, Tris-HCl (10 mM, pH 7.4), protease inhibitors (Complete Protease Inhibitor Cocktail, Roche) and phosphatase inhibitors (0.1 mM Na3VO4, 1 mM NaF). The homogenates were sonicated for 2 min and centrifuged at 100,000×g for 1 h. Aliquots of supernatant were directly diluted and loaded onto ELISA plates in duplicate. The assays were performed according to the manufacturer’s instructions.
For Western blot analysis of APP-derived fragments, SDS 2 % protein extracts were separated in a CriterionTM Tris-Tricine 10–20 % gradient precast gel (Bio-Rad, Hercules, CA, USA). For analysis of pTau and Tau, proteins were separated in a Criterion TM Bis-Tris 4–12 % gradient precast gel (Bio-Rad, Hercules, CA, USA). For further details, see Additional file 1: Additional methods.
Dendritic spine measurements
Data analysis and statistical procedures
The data was analyzed with SPSS for Windows, version 15.0 (SPSS, Chicago, IL, USA), and unless otherwise indicated, the data is expressed as means ± standard error of the mean (S.E.M.). Normal distribution of data was checked by the Shapiro-Wilk test.
In the MWM, latencies to find the platform were examined by a two-way repeated measures ANOVA test (genotype × trial) to compare the cognitive status in WT mice and Tg2576 mice. Likewise, the treatment effect in spatial memory was examined also by a two-way repeated measures ANOVA test (treatment × trial) followed by post hoc Scheffe’s analysis. In those cases where no interaction was found between factors, the F value associated to genotype or treatment main effect will be shown. When two groups were compared, Student’s t test was used, whereas when more than two experimental groups were compared, one-way ANOVA followed by post hoc Scheffe’s test was used. Each biochemical assay was repeated, at least, three times, and the data were analyzed using one-way ANOVA followed by post hoc Scheffe’s test.
amyloid precursor protein
Morris water maze
We thank Maria Espelosin and Susana Ursua for their work in the animal facility and cell culture. This study was supported by FIMA (Spain), the FIS project (11/02861 and 14/01244) to AGO, MINECO (Ramón y Cajal Program, RYC-2012-12014, and BFU2013-47265R) to G.P and a Torres Quevedo grant (from MINECO PTQ-12-05641) to AU.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Graff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 2012;483:222–6.PubMed CentralView ArticlePubMedGoogle Scholar
- Srividya S, Bates SE, Wright JJ, Igor E-D, Piekarz RL. Clinical toxicities of histone deacetylase inhibitors. Pharmaceuticals. 2010;3:2751–67.View ArticleGoogle Scholar
- Kwon P, Hsu M, Cohen D, Atadja P. HDAC inhibitors. In: Histone deacetylases: transcriptional regulation and other cellular functions, E. V., editor. Totowa, NJ: Humana; 2006. p. 315–32.View ArticleGoogle Scholar
- Garcia-Osta A, Cuadrado-Tejedor M, Garcia-Barroso C, Oyarzabal J, Franco R. Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem Neurosci. 2012;3:832–44.PubMed CentralView ArticlePubMedGoogle Scholar
- Heckman PR, Blokland A, Ramaekers J, Prickaerts J. PDE and cognitive processing: beyond the memory domain. Neurobiol Learn Mem. 2015;119:108–22.View ArticlePubMedGoogle Scholar
- Heckman PR, Wouters C, Prickaerts J. Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimer’s disease: a translational overview. Curr Pharm Des. 2015;21:317–31.View ArticlePubMedGoogle Scholar
- Lu YF, Kandel ER, Hawkins RD. Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. J Neurosci. 1999;19:10250–61.PubMedGoogle Scholar
- Benito E, Barco A. CREB’s control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models. Trends Neurosci. 2010;33:230–40.View ArticlePubMedGoogle Scholar
- Silva AJ, Kogan JH, Frankland PW, Kida S. CREB and memory. Annu Rev Neurosci. 1998;21:127–48.View ArticlePubMedGoogle Scholar
- Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J Neurosci. 2007;27:6128–40.PubMed CentralView ArticlePubMedGoogle Scholar
- Fass DM, Reis SA, Ghosh B, Hennig KM, Joseph NF, Zhao WN, et al. Crebinostat: a novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity. Neuropharmacology. 2013;64:81–96.PubMed CentralView ArticlePubMedGoogle Scholar
- Graff J, Tsai LH. The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol. 2013;53:311–30.View ArticlePubMedGoogle Scholar
- Fischer A, Sananbenesi F, Mungenast A, Tsai LH. Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci. 2010;31:605–17.View ArticlePubMedGoogle Scholar
- Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH. Recovery of learning and memory is associated with chromatin remodelling. Nature. 2007;447:178–82.View ArticlePubMedGoogle Scholar
- Paulsen O, Sejnowski TJ. Natural patterns of activity and long-term synaptic plasticity. Curr Opin Neurobiol. 2000;10:172–9.PubMed CentralView ArticlePubMedGoogle Scholar
- Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2010;35:870–80.PubMed CentralView ArticlePubMedGoogle Scholar
- Garcia-Barroso C, Ricobaraza A, Pascual-Lucas M, Unceta N, Rico AJ, Goicolea MA, et al. Tadalafil crosses the blood–brain barrier and reverses cognitive dysfunction in a mouse model of AD. Neuropharmacology. 2013;64:114–23.View ArticlePubMedGoogle Scholar
- Ricobaraza A, Cuadrado-Tejedor M, Marco S, Perez-Otano I, Garcia-Osta A. Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus. 2012;22:1040–50.View ArticlePubMedGoogle Scholar
- Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.PubMed CentralView ArticlePubMedGoogle Scholar
- Reichenberg A, Mill J, MacCabe JH. Epigenetics, genomic mutations and cognitive function. Cogn Neuropsychiatry. 2009;14:377–90.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6:38–51.View ArticlePubMedGoogle Scholar
- Rumbaugh G, Sillivan SE, Ozkan ED, Rojas CS, Hubbs CR, Aceti M, et al. Pharmacological selectivity within class I histone deacetylases predicts effects on synaptic function and memory rescue. Neuropsychopharmacology. 2015;40:2307–16.View ArticlePubMedGoogle Scholar
- Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature. 2009;459:55–60.PubMed CentralView ArticlePubMedGoogle Scholar
- Kazantsev AG, Thompson LM. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov. 2008;7:854–68.View ArticlePubMedGoogle Scholar
- Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature. 1993;365:855–9.View ArticlePubMedGoogle Scholar
- Smolen P, Baxter DA, Byrne JH. Simulations suggest pharmacological methods for rescuing long-term potentiation. J Theor Biol. 2014;360:243–50.View ArticlePubMedGoogle Scholar
- Cuadrado-Tejedor M, Hervias I, Ricobaraza A, Puerta E, Perez-Roldan JM, Garcia-Barroso C, et al. Sildenafil restores cognitive function without affecting Ass burden in an Alzheimer’s disease mouse model. Br J Pharmacol. 2011;164:2029–41.PubMed CentralView ArticlePubMedGoogle Scholar
- Ding H, Dolan PJ, Johnson GV. Histone deacetylase 6 interacts with the microtubule-associated protein tau. J Neurochem. 2008;106:2119–30.PubMed CentralView ArticlePubMedGoogle Scholar
- Xiong Y, Zhao K, Wu J, Xu Z, Jin S, Zhang YQ. HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila. Proc Natl Acad Sci U S A. 2013;110:4604–9.PubMed CentralView ArticlePubMedGoogle Scholar
- Boyault C, Sadoul K, Pabion M, Khochbin S. HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene. 2007;26:5468–76.View ArticlePubMedGoogle Scholar
- Boyault C, Zhang Y, Fritah S, Caron C, Gilquin B, Kwon SH, et al. HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev. 2007;21:2172–81.PubMed CentralView ArticlePubMedGoogle Scholar
- Sung YM, Lee T, Yoon H, Dibattista AM, Song JM, Sohn Y, 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. 2012;239C:192–201.Google Scholar
- Zhang L, Liu C, Wu J, Tao JJ, Sui XL, Yao ZG, et al. Tubastatin A/ACY-1215 improves cognition in Alzheimer’s disease transgenic mice. J Alzheimers Dis. 2014;41(4):1193–205.PubMedGoogle Scholar
- Ricobaraza A, Cuadrado-Tejedor M, Perez-Mediavilla A, Frechilla D, Del Rio J, Garcia-Osta A. Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacology. 2009;34:1721–32.View ArticlePubMedGoogle Scholar
- Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996;274:99–102.View ArticlePubMedGoogle Scholar
- Steinerman JR, Irizarry M, Scarmeas N, Raju S, Brandt J, Albert M, et al. Distinct pools of beta-amyloid in Alzheimer disease-affected brain: a clinicopathologic study. Arch Neurol. 2008;65:906–12.PubMed CentralView ArticlePubMedGoogle Scholar
- Glaser EM, Van der Loos H. Analysis of thick brain sections by obverse-reverse computer microscopy: application of a new, high clarity Golgi-Nissl stain. J Neurosci Methods. 1981;4:117–25.View ArticlePubMedGoogle Scholar