ArticleAlzheimer's research & therapy2024
Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the APP/PS1 Alzheimer's disease mouse model by regulating the expression of APP secretases.
Article in Alzheimer's research & therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 31 citations in OpenAlex.
- miR-584-5p suppresses AβActa neurologica Belgica · 2026Article
- The neuroprotective effect of Cucurbitacin B against Aβ and tau toxicities requires functional HDAC6 and stress granule pathways.Biogerontology · 2026Article
- Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice.Journal of nanobiotechnology · 2026Article
- The relationship between gut microbiota and neurodegenerative diseases: a genetic and epigenetic perspective.Metabolic brain disease · 2026Review
- Aerobic exercise facilitates p300 nuclear translocation via ADRB2-AMPKα signaling, leading to enhanced histone acetylation and mitigation of cognitive decline in APP/PS1 mice.Alzheimer's research & therapy · 2026Article
- HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-Type Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- The Molecular Architecture of Neurodegeneration: An Integrative Overview of Convergent Mechanisms.NeuroSci · 2026Review
- Ramalin Ameliorates Alzheimer's Disease Pathology by Targeting BACE1, HDAC6, and MAPK Pathways.MedComm · 2026Article
- Microbial SCFAs as epigenetic mediators: fine-tuning the gut-brain axis in neurodegenerative disorders.Current research in microbial sciences · 2026Review
- Integrating imaging and omics for enhanced subtyping of mild cognitive impairment associated with Alzheimer's disease.Journal of translational medicine · 2025Article
- Beyond epilepsy: The expanding role of valproic acid in Alzheimer disease therapy - a review.The Journal of pharmacology and experimental therapeutics · 2025Review
- Review
- Evaluation of the Effects of Thymoquinone on RAGE/NOX4 Expressions and Brain Tissue Morphometry in Experimental Alzheimer's Disease Induced by Amyloid Beta 1-42 Peptide.Biomolecules · 2025Article
- Contilisant-Belinostat Hybrids: Polyfunctionalized Indole Derivatives as Multineurotarget Drugs for the Potential Treatment of Alzheimer's Disease.ACS pharmacology & translational science · 2025Article
- A Novel Histone Deacetylase 6 Inhibitor, 4-FHA, Improves Scopolamine-Induced Cognitive and Memory Impairment in Mice.Biomolecules & therapeutics · 2025Article
- The Promise of Epigenetic Editing for Treating Brain Disorders.Sub-cellular biochemistry · 2025Review
- Histone Deacetylase Inhibition in Alzheimer's Disease: Molecular Mechanisms, Therapeutic Potential, and Future Perspectives.Current topics in medicinal chemistry · 2025Review
- Shen Zhi Ling oral liquid improve neuroinflammation against Alzheimer's disease via the PI3K/Akt pathway.3 Biotech · 2025Article
- Review
- Identification of JAZF1, KNOP1, and PLEKHA1 as causally associated genes and drug targets for Alzheimer's disease: a summary data-based Mendelian randomization study.Inflammopharmacology · 2024Article
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundAlzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated.
methodsA cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. LC-MS/MS was applied to quantify the concentration of WT161 in the mouse brain. Western blotting, immunohistochemical staining, thioflavin-S staining and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test and Morris water maze test.
resultsPrevious studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aβ deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice.
conclusionsIn general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD.
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