Cited by 137Alzheimer's disease research and treatmentsHistone Deacetylase Inhibitors ResearchCholinesterase and Neurodegenerative Diseases

The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index; 4 of the 6 sources its claims cite were checked for support.

Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease

Open access

Abstract

Histone deacetylase inhibitors (HDACIs) alter gene expression epigenetically by interfering with the normal functions of HDAC. Given their ability to decrease Aβ levels, HDACIs area potential treatment for Alzheimer's disease (AD). However, it is unclear how HDACIs alter Aβ levels. We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood-brain barrier: mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as I2) and investigated how they affect Aβ levels and cognition. HDACI W2 decreased Aβ40 and Aβ42 in vitro. HDACI I2 also decreased Aβ40, but not Aβ42. We systematically examined the molecular mechanisms by which HDACIs W2 and I2 can decrease Aβ levels. HDACI W2 decreased gene expression of γ-secretase components and increased the Aβ degradation enzyme Mmp2. Similarly, HDACI I2 decreased expression of β- and γ-secretase components and increased mRNA levels of Aβ degradation enzymes. HDACI W2 also significantly decreased Aβ levels and rescued learning and memory deficits in aged hAPP 3x Tg AD mice. Furthermore, we found that the novel HDACI W2 decreased tau phosphorylation at Thr181, an effect previously unknown for HDACIs. Collectively, these data suggest that class II HDACls may serve as a novel therapeutic strategy for AD.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Novel mercaptoacetamide-based class II HDAC inhibitor W2 lowers Aβ levels, reduces tau phosphorylation at Thr181, and improves learning and memory in hAPP 3xTg AD mice. The study also identifies transcriptional downregulation of Aβ-producing enzymes and upregulation of Aβ-degrading enzymes as possible mechanisms.

Key findings

  • In N2a-APP cells, W2 decreased human Aβ40 and Aβ42 by 20%, while I2 significantly decreased Aβ40 but not Aβ42; W2 or I2 also decreased rodent Aβ40 by 20% in primary cortical neurons.
  • W2 increased cell surface APP by 33% at 2 hrs and both W2 and I2 increased it about twofold at 24 hrs; in vivo, W2 increased sAPPα and decreased sAPPβ.
  • In 9–10 month old hAPP 3xTg AD mice, W2 (50 mg/kg daily i.p.) decreased soluble Aβ40 after 2 weeks and decreased soluble and insoluble Aβ40 and Aβ42 after 4 weeks; W2 also reduced Thr181 phospho-tau by approximately 50% without changing total tau or tau kinases.
  • W2 improved learning and memory in wild-type mice and rescued cognitive deficits in 9–10 month old hAPP 3xTg AD mice, as shown by increased platform crossings without altered swim speed.

Methods

  • In vitro: N2a cells overexpressing hAPP, primary rat cortical and hippocampal neurons, Aβ ELISA, cell surface biotinylation, live cell surface staining, and qPCR for Aβ synthesis/degradation genes.
  • In vivo: 9–10 month old hAPP 3xTg AD mice and 2–3 month old wild-type mice received W2 (50 mg/kg, daily i.p.) or control for 2 or 4 weeks; brain Aβ was measured by DEA/FA fractionation and ELISA, with immunoblotting for APP cleavage products and tau phosphorylation.
  • Behavior: Morris water maze assessed spatial learning and memory; statistics used two-tailed t-tests or one-way ANOVA with Tukey’s post-hoc, and two-way ANOVA for escape latencies, with significance at p<0.05.

Limitations

  • The paper states that the lowest optimal dose of HDACIs and additional molecular mechanisms affecting cognitive performance are still being investigated.
  • Evident from the text: I2 was not tested in vivo; W2 was selected for in vivo work because it was more effective in reducing Aβ in vitro, so the in vivo findings apply only to W2.
  • Evident from the text: the study reports cognitive rescue in the 3xTg AD model but does not establish whether the effects generalize to other AD models or to human AD.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.expneurol.2012.10.005

Cites

28 of 28 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

4 of 6 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

Show all 22 claims

  • It may state two separate claims as one. 10
  • Probably not a substantial claim. 1
  • The quote only partly states this claim. 1
12 of 12
  • The paper relies on this without support.

    HDAC inhibitors alter gene expression epigenetically by interfering with normal HDAC functions.

    “Histone deacetylase inhibitors (HDACIs) alter gene expression epigenetically by interfering with the normal functions of HDAC.”
  • The paper relies on this without support.

    Commercially available HDACIs have poor pharmacological properties.

    “However, these commercially available HDACIs have poor pharmacological properties.”
  • The paper relies on this without support.

    9-10 month old hAPP 3xTg AD mice exhibit mild cognitive impairment.

    “we injected 9-10 month old hAPP 3x Tg AD mice (with mild cognitive impairment) for 4 weeks with W2 (50 mg/kg, daily i.p.) or control.”
  • The paper relies on this without support.

    Findings in mouse models of AD translate to therapeutic benefit in human dementias, including AD.

    “Taken together, these data demonstrate that our novel compound Class II HDACI W2 mayhave the potential toalleviatecritical neuropathogenic processes in dementias, including AD, providing broad-spectrum therapeutic benefits.”
  • The paper relies on this without support.

    Changes in mRNA levels of Aβ synthesis and degradation enzymes lead to corresponding changes in enzyme activity and Aβ clearance.

    “Taken together, our data suggest that our novel compounds have dual effects of down-regulating Aβ production pathways while simultaneously up-regulating Aβ clearance mechanisms.”
  • The paper relies on this without support.

    W2 and I2 inhibit HDACs in the tested systems.

    “HDAC inhibition decreased expression of genes involved in Aβ production and induced expression of Aβ degradation enzymes.”
6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • HDACI effects on tau phosphorylation described as unknown despite cited prior finding

    Minor

    The results state that it was unknown whether HDAC inhibitors could alter tau phosphorylation, but the discussion describes a prior HDACI finding that decreased phosphorylated tau at Thr231.

1 of 1

Citations

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Metadata

Authors
Sung, Y. M., Lee, T., Yoon, H., DiBattista, A. M., Song, J. M., Sohn, Y., Moffat, E. I., Turner, R. S., Jung, M., Kim, J., & Hoe, H.-S.
Affiliations
  • Seoul National University (KR)
  • Georgetown University Medical Center (US)
  • Washington University in St. Louis (US)
Corresponding author
  • Kim, Jungsu
  • Hoe, Hyang-Sook
Venue
Experimental Neurology
Publisher
Elsevier BV
Published
2013-01
Volume
239
Pages
192-201
ISSN
0014-4886 (ISSN-L)
OpenAlex
W2080228122
Cited by
137
References
28
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 8 · 2022: 4 · 2021: 10 · 2020: 19 · 2019: 7 · 2018: 9 · 2017: 14 · 2016: 11 · 2015: 14 · 2014: 16 · 2013: 7
FWCI
6.98
Type
journal article
Language
en
Open access
Locations
  • Experimental Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • NIH (AG034253, AG039708, AG026478, P30NS069329)
  • M4M Recipient of Young investigator award
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
Keywords
histone deacetylase inhibitors, Alzheimer's disease, amyloid-beta, gamma-secretase, MMP-2, learning and memory, tau phosphorylation, blood-brain barrier penetration, epigenetic therapy
MeSH terms
Acetamides, Alzheimer Disease, Animals, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Humans, Learning, Memory, Mice, Transgenic, Microinjections, Neurons, Phosphorylation, Thioglycolates, Transfection, Blotting, Western, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Maze Learning, Mice, Histone Deacetylase 2, Histone Deacetylase Inhibitors, Real-Time Polymerase Chain Reaction

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