trichostatin-a and Alzheimer-Disease

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, which is characterized by the primary risk factor, age. Several attempts have been made to treat AD, while most of them end in failure. However, with the deepening study of pathogenesis of AD, the expression of HDAC6 in the hippocampus, which plays a major role of the memory formation, is becoming worth of notice. Neurofibrillary tangles (NFTs), a remarkable lesion in AD, has been characterized in association with the abnormal accumulation of hyperphosphorylated Tau, which is mainly caused by the high expression of HDAC6. On the other hand, the hypoacetylated tubulin induced by HDAC6 is also fatal for the neuronal transport, which is the key impact of the formation of axons and dendrites. Overall, the significantly increased expression of HDAC6 in brain regions is deleterious to neuron survival in AD patients. Based on the above research, the inhibition of HDAC6 seems to be a potential therapeutic method for the treatment of AD. Up to now, various types of HDAC6 inhibitors have been discovered. This review mainly analyzes the HDAC6 inhibitors reported amid 2010-2020 in terms of their structure, selectivity and pharmacological impact towards AD. And we aim at facilitating the design and development of better HDAC6 inhibitors in the future.

Topics: Acetamides; Alzheimer Disease; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Models, Molecular; Molecular Structure; Neuroprotective Agents

Chlamydia pneumoniae (Cpn) is a gram-negative intracellular pathogen that causes a variety of pulmonary diseases, and there is growing evidence that it may play a role in Alzheimer's disease (AD) pathogenesis. Cpn can interact functionally with host histones, altering the host's epigenetic regulatory system by introducing bacterial products into the host tissue and inducing a persistent inflammatory response. Because Cpn is difficult to propagate, isolate, and detect, a modified LPS-like neuroinflammation model was established using lyophilized cell free supernatant (CFS) obtained from infected cell cultures, and the effects of CFS were compared to LPS. The neuroprotective effects of Trichostatin A (TSA), givinostat, and RG108, which are effective on epigenetic mechanisms, and the antibiotic rifampin, were studied in this newly introduced model and in the presence of amyloid beta (Aβ) 1-42. The neuroprotective effects of the drugs, as well as the effects of CFS and LPS, were evaluated in Aβ-induced neurotoxicity using a real-time cell analysis system, total ROS, and apoptotic impact. TSA, RG108, givinostat, and rifampin all demonstrated neuroprotective effects in both this novel model and Aβ-induced neurotoxicity. The findings are expected to provide early evidence on neuroprotective actions against Cpn-induced neuroinflammation and Aβ-induced neurotoxicity, which could represent a new treatment option for AD, for which there are currently few treatment options.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Carbamates; Chlamydophila Infections; Chlamydophila pneumoniae; Epigenesis, Genetic; Humans; Hydroxamic Acids; Inflammation; Neuroprotective Agents; Peptide Fragments; Phthalimides; THP-1 Cells; Tryptophan

Alzheimer's disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms.. Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS.. TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers.. These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.

Topics: Aged; Albumins; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Chromatography, Liquid; Cognition; Disease Models, Animal; Endothelial Cells; Humans; Hydroxamic Acids; Mice; Mice, Transgenic; Presenilin-1; Tandem Mass Spectrometry

We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.

Topics: Alzheimer Disease; Cell Line; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Drug Design; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Molecular Structure; Neuroglia; Phosphodiesterase 5 Inhibitors; Structure-Activity Relationship

This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1 H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC

Topics: Alzheimer Disease; Animals; Binding Sites; Blood-Brain Barrier; Cell Line; Disease Models, Animal; Female; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Male; Memory and Learning Tests; Mice, Transgenic; Molecular Docking Simulation; Neuroprotective Agents; Phosphorylation; Rats, Sprague-Dawley; Rats, Wistar; tau Proteins; Ubiquitination

Histone deacetylases (HDACs) are promising therapeutic targets for neurological and psychiatric disorders that impact cognitive ability, but the relationship between various HDAC isoforms and cognitive improvement is poorly understood, particularly in mouse models of memory impairment. A goal shared by many is to develop HDAC inhibitors with increased isoform selectivity in order to reduce unwanted side effects, while retaining procognitive effects. However, studies addressing this tack at the molecular, cellular and behavioral level are limited. Therefore, we interrogated the biological effects of class I HDAC inhibitors with varying selectivity and assessed a subset of these compounds for their ability to regulate transcriptional activity, synaptic function and memory. The HDAC-1, -2, and -3 inhibitors, RGFP963 and RGFP968, were most effective at stimulating synaptogenesis, while the selective HDAC3 inhibitor, RGFP966, with known memory enhancing abilities, had minimal impact. Furthermore, RGFP963 increased hippocampal spine density, while HDAC3 inhibition was ineffective. Genome-wide gene expression analysis by RNA sequencing indicated that RGFP963 and RGFP966 induce largely distinct transcriptional profiles in the dorsal hippocampus of mature mice. The results of bioinformatic analyses were consistent with RGFP963 inducing a transcriptional program that enhances synaptic efficacy. Finally, RGFP963, but not RGFP966, rescued memory in a mouse model of Alzheimer's Disease. Together, these studies suggest that the specific memory promoting properties of class I HDAC inhibitors may depend on isoform selectivity and that certain pathological brain states may be more receptive to HDAC inhibitors that improve network function by enhancing synapse efficacy.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Animals, Newborn; Cells, Cultured; Conditioning, Psychological; Disease Models, Animal; Fear; Gene Expression Profiling; Green Fluorescent Proteins; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurons; Presenilin-1; Synapses; Synaptophysin

Gelsolin (GSN), a multifunctional protein, binds to amyloid beta-protein (Aβ), inhibits its fibrillization, solubilizes preformed Aβ fibrils, and helps in its clearance from the brain. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, induces the protein expression of gelsolin. In the present study, we investigated how TSA-treatment of APPswe/PS1δE9 transgenic (Tg) mice of Alzheimer's disease (AD) will affect the plasma levels of gelsolin and Aβ.. TSA (5mg/kg body weight on alternate days for two months) was intraperitoneally injected to AD Tg mice. Gelsolin was measured by Western blotting and Aβ was measured by enzyme-linked immunosorbent assay.. TSA-treatment significantly increased the levels of plasma gelsolin by 1.79-fold as compared with vehicle-treated control mice (p<0.01). The levels of Aβ 1-40 and Aβ 1-42 in the plasma were also higher in TSA-treated mice in comparison with vehicle-treated mice. The treatment of transgenic AD mice with TSA did not affect the body weight in both male and female groups as compared to vehicle-treated animals. A positive correlation was observed between the plasma levels of gelsolin and Aβ 1-40 (r=0.594, p=0.042) or Aβ 1-42 (r=0.616, p=0.033) in AD Tg mice.. These results suggest that TSA increases the levels of plasma gelsolin and Aβ in AD Tg mice, which may have implications in gelsolin-mediated clearance of Aβ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blotting, Western; Body Weight; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Gelsolin; Gene Expression Regulation; Hydroxamic Acids; Infusions, Parenteral; Male; Mice; Mice, Transgenic; Peptide Fragments; Protein Synthesis Inhibitors

In vivo and in vitro studies have shown that gelsolin is an anti-amyloidogenic protein. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the expression of gelsolin. Fibrillized amyoid beta-protein (Aβ) is a key constituent of amyloid plaques in the brains of patients with Alzheimer's disease (AD). We studied the effects of TSA on the levels of gelsolin; amyloid precursor protein (APP); proteolytic enzymes (γ-secretase and β-secretase) responsible for the production of Aβ; Aβ-cleaving enzymes, i.e., neprilysin (NEP) and insulin-degrading enzyme (IDE); and amyloid load in the double transgenic (Tg) APPswe/PS1(δE9) mouse model of AD. Intraperitoneal injection of TSA for two months (9-11 months of age) resulted in decreased activity of HDAC, and increased levels of gelsolin in the hippocampus and cortex of the brain in AD Tg mice as compared to vehicle-treated mice. TSA also increased the levels of γ-secretase and β-secretase activity in the brain. However, TSA did not show any effect on the activities or the expression levels of NEP and IDE in the brain. Furthermore, TSA treatment of AD Tg mice showed no change in the amyloid load (percent of examined area occupied by amyloid plaques) in the hippocampus and cortex, suggesting that TSA treatment did not result in the reduction of amyloid load. Interestingly, TSA prevented the formation of new amyloid deposits but increased the size of existing plaques. TSA treatment did not cause any apoptosis in the brain. These results suggest that TSA increases gelsolin expression in the brain, but the pleiotropic effects of TSA negate the anti-amyloidogenic effect of gelsolin in AD Tg mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Female; Gelsolin; Gene Expression Regulation; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; In Situ Nick-End Labeling; Male; Mice; Mice, Transgenic; Mutation; Presenilin-1

The mechanisms by which environmental influences lead to the development of complex neurodegenerative diseases are largely unknown. It is known, however, that epigenetic mechanisms can mediate alterations in transcription due to environmental influences. In order to identify genes susceptible to regulation in the adult cortex by one type of epigenetic mechanism, histone, and protein acetylation, we treated mice with the histone deacetylase inhibitor Trichostatin A (TSA). After 1 week of treatment with TSA, RNA was extracted from the brain cortices of mice and gene expression differences were analyzed by microarray profiling. The altered genes were then compared with genes differentially expressed in microarray studies of disease by database and literature searches. Genes regulated by TSA were found to significantly overlap with differentially expressed genes in the Alzheimer's disease (AD) brain. Several TSA-regulated genes involved in chromatin remodeling and epigenetic reprogramming including histone cluster 1, H4 h (Hist1H4 h), methionine adenosyltransferase II, alpha (Mat2a), and 5-methyltetrahydrofolate homocysteine reductase (Mtrr) overlapped with genes altered in early-stage AD in gray matter. We also show that the expression of hemoglobin, which has been shown to be altered in neurons in the AD brain, is regulated by TSA treatment. This analysis suggests involvement of epigenetic mechanisms in neurons in early stages of AD.

Topics: Acetylation; Alzheimer Disease; Animals; Cerebral Cortex; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Hydroxamic Acids; Male; Mice; Mice, Inbred C57BL; Tissue Array Analysis; Transcription, Genetic

Thyroid hormone (T3) suppresses cerebral gene expression of the β-amyloid precursor protein (APP), an integral membrane protein that plays a key role in the onset and progression of Alzheimer's disease. However, the mechanisms by which T3 signaling pathways inhibit APP gene transcription in the brain remain unclear. By carrying out chromatin immunoprecipitation with neuroblastoma cells and primary rat brain tissue, we show for the first time that thyroid hormone receptors (TRs) directly bind at the APP gene in vivo at a promoter region containing a negative T3-response element. We further show that T3 treatment decreases both histone H3 acetylation and histone H3 lysine 4 methylation at the APP promoter and that chemical inhibitors of histone deacetylases and histone lysine demethylase abrogate T3-dependent APP silencing. Our findings thus suggest that TRs actively facilitate T3-dependent silencing of APP gene expression via the recruitment of distinct histone modifying enzymes associated with transcriptional repression.

Topics: Acetylation; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Cell Line, Tumor; Epigenesis, Genetic; Gene Expression Regulation; Histone Deacetylase Inhibitors; Histone Demethylases; Histones; Humans; Hydroxamic Acids; Male; Methylation; Promoter Regions, Genetic; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Receptors, Thyroid Hormone; Tranylcypromine; Triiodothyronine