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Cited by 38Alzheimer's disease research and treatmentsMitochondrial Function and PathologyHistone Deacetylase Inhibitors Research

Reduction of class I histone deacetylases ameliorates ER ‐mitochondria cross‐talk in Alzheimer's disease

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Marinho, Daniela, Ferreira, Ildete Luísa, Lorenzoni, Ricardo, Cardoso, Sandra M., Santana, Isabel, Rego, A. Cristina·2023·Aging Cell
DOI 10.1111/acel.13895PMC PMC10410063
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Abstract

Several molecular mechanisms have been described in Alzheimer's disease (AD), including repressed gene transcription and mitochondrial and endoplasmic reticulum (ER) dysfunction. In this study, we evaluate the potential efficacy of transcriptional modifications exerted by inhibition or knockdown of class I histone deacetylases (HDACs) in ameliorating ER‐mitochondria cross‐talk in AD models. Data show increased HDAC3 protein levels and decreased acetyl‐H3 in AD human cortex, and increased HDAC2‐3 in MCI peripheral human cells, HT22 mouse hippocampal cells exposed to Aβ 1–42 oligomers (AβO) and APP/PS1 mouse hippocampus. Tacedinaline (Tac, a selective class I HDAC inhibitor) counteracted the increase in ER‐Ca 2+ retention and mitochondrial Ca 2+ accumulation, mitochondrial depolarization and impaired ER‐mitochondria cross‐talk, as observed in 3xTg‐AD mouse hippocampal neurons and AβO‐exposed HT22 cells. We further demonstrated diminished mRNA levels of proteins involved in mitochondrial‐associated ER membranes (MAM) in cells exposed to AβO upon Tac treatment, along with reduction in ER‐mitochondria contacts (MERCS) length. HDAC2 silencing reduced ER‐mitochondria Ca 2+ transfer and mitochondrial Ca 2+ retention, while knockdown of HDAC3 decreased ER‐Ca 2+ accumulation in AβO‐treated cells. APP/PS1 mice treated with Tac (30 mg/kg/day) also showed regulation of mRNA levels of MAM‐related proteins, and reduced Aβ levels. These data demonstrate that Tac normalizes Ca 2+ signaling between mitochondria and ER, involving the tethering between the two organelles in AD hippocampal neural cells. Tac‐mediated AD amelioration occurs through the regulation of protein expression at MAM, as observed in AD cells and animal models. Data support transcriptional regulation of ER‐mitochondria communication as a promising target for innovative therapeutics in AD.

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  • CI-994 is a molecular memory aid and promotes memory formation and cognitive function in vivo.

    “CI-994 is a molecular memory aid and promotes memory formation and cognitive function in vivo [9, 17, 21–24].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [9]

    The Introduction (page unavailable) identifies tacedinaline as CI-994 and reports improved cognitive and memory dysfunction in two mouse models, supporting an in vivo memory and cognition benefit. It does not establish that CI-994 promotes memory formation specifically; the paper’s own in vivo results measure hippocampal pathology and molecular changes, not memory formation. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • CI-994 alleviates cognitive deficits in mouse models of neurodegenerative disorders.

    “CI-994 acts as a memory enhancer and alleviates cognitive deficits in mouse models of neurodegenerative disorders [9, 17, 21–24].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [9]

    The Discussion (page not provided) reports that CI-994, called Tac in the paper, improved cognition in an intellectual-disability mouse model and reduced drug-induced memory impairment in aged mice. The Results report reduced amyloid-β in APP/PS1 Alzheimer’s mice, but do not report a cognitive assessment in those mice. The cited paper therefore does not establish that CI-994 alleviates cognitive deficits in mouse models of neurodegenerative disorders. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • CI-994 acts as a memory enhancer in mouse models of neurodegenerative disorders.

    “CI-994 acts as a memory enhancer and alleviates cognitive deficits in mouse models of neurodegenerative disorders [9, 17, 21–24].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [9]

    The Discussion (page unavailable) reports that tacedinaline (CI-994) improved cognition in an intellectual-disability mouse model and reduced drug-induced memory impairment in aged mice. Neither is identified as a mouse model of a neurodegenerative disorder. The paper also reports CI-994 treatment of APP/PS1 Alzheimer’s mice in the Results, but reports biochemical changes rather than a measured memory benefit. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Small molecule inhibitors of class I HDACs can alleviate memory deficits in mouse AD models.

    “small molecule inhibitors of class I HDACs can alleviate memory deficits in mouse AD models [9–11].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [9]

  • CI-994 is a cognitive enhancer / improves cognitive function.

    “CI-994 can cross the blood–brain barrier and is a cognitive enhancer.”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [9]

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Cited by

Sorted by citations

Authors
Marinho, D., Ferreira, I. L., Lorenzoni, R., Cardoso, S. M., Santana, I., & Rego, A. C.
Affiliations
  • Centro de Neurociências e Biologia Celular (PT)
  • Unidade Local de Saúde de Coimbra (PT)
Corresponding author
  • Ferreira, Ildete Luísa
  • Rego, A. Cristina
ORCID
Venue
Aging Cell
Publisher
Wiley
Published
2023-06-26
Volume
22
Issue
8
Pages
e13895-e13895
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
DOI
10.1111/acel.13895
PMC
PMC10410063
OpenAlex
W4382011898
Cited by
38
References
6
Citations by year
2026: 8 · 2025: 18 · 2024: 8 · 2023: 3 · 2019: 1
FWCI
6.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by)
Funders
  • European Regional Development Fund (CENTRO‐01‐0145‐FEDER‐000012‐HealthyAging2020)
  • Fundação para a Ciência e a Tecnologia (LA/P/0058/2020, POCI‐01‐0145‐FEDER‐032316, PhD fellowship 2020.07951.BD, UIDB/04539/2020, UIDP/04539/2020)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Keywords
Alzheimer's disease, class I histone deacetylases, HDAC3, HDAC2, calcium signaling, amyloid-beta oligomers, APP/PS1 mice, HT22 cells, mitochondrial depolarization, transcriptional regulation
MeSH terms
Alzheimer Disease, Animals, Endoplasmic Reticulum, Histone Deacetylases, Humans, Mitochondria, Amyloid beta-Peptides, Mice

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