Inhibition of HDAC6 expression decreases brain injury induced by APOE4 and Aβ co‑aggregation in rats
Open accessAbstract
The present study aimed to explore the effects of histone deacetylase 6 (HDAC6) on brain injury in rats induced by apolipoprotein E4 (APOE4) and amyloid β protein alloform 1‑40 (Aβ1‑40) copolymerization. The rats were randomly divided into four groups: Control group, sham group, APOE4 + Aβ1‑40 co‑injection group (model group) and HDAC6 inhibitor group (HDAC6 group). The brain injury model was established by co‑injection of APOE4 + Aβ1‑40. Morris water maze experiment was used to observe the spatial memory and learning the ability of rats. Histological changes of the hippocampus were observed by hematoxylin and eosin staining. The mRNA expression levels of choline acetyltransferase (ChAT) and HDAC6 were detected by reverse transcription‑quantitative PCR. Immunohistochemistry was used to detect the protein expression of HDAC6. Western blotting was used to detect the protein expression levels of HDAC6, microtubule‑associated protein tau and glycogen synthase kinase 3β (GSK3β). APOE4 and Aβ1‑40 co‑aggregation decreased the short‑term spatial memory and learning ability of rats, whereas inhibition of HDAC6 activity attenuated the injury. Inhibition of HDAC6 activity resulted in an attenuation of the APOE4 and Aβ1‑40 co‑aggregation‑induced increase in the number of dysplastic hippocampal cells. Further experiments demonstrated that APOE4 and Aβ1‑40 co‑aggregation decreased the expression levels of ChAT mRNA, and the phosphorylation levels of tau GSK3β protein in the hippocampus, whereas inhibition of HDAC6 activity resulted in increased expression of ChAT mRNA, tau protein and GSK3β phosphorylation. The inhibition of HDAC6 activity was also demonstrated to reduce brain injury induced by APOE4 and Aβ1‑40 co‑aggregation in model rats.
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ApoE4 is associated with decreased dendritic spine density and dendrite length, inhibition of neurite outgrowth and impaired neuronal plasticity, particularly in hippocampal pyramidal neurons.
“Another ApoE4-mediated effect at the synaptic level, are the decreased dendritic spine density and dendrite length, inhibition of neurite outgrowth and impaired neuronal plasticity [43], particularly in hippocampal pyramidal neurons [38].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [38]
The Introduction states that ApoE4 may inhibit hippocampal synaptic plasticity, supporting the plasticity part of the claim. Our copy does not report decreased dendritic spine density or dendrite length, or inhibited neurite outgrowth. The phrase about hippocampal pyramidal neurons has a separate citation [38] in the citing sentence and is not assessed against this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredApoE4 directly interacts with both soluble and fibrillar forms of Aβ, accelerating its oligomerization and deposition in the brain.
“ApoE4 is able to directly interact with both soluble and fibrillar forms of Aβ [17,38], accelerating its oligomerization and deposition in the brain [2].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [38]
The Introduction (page not available) reports that APOE4 enhances Aβ fibril formation and accelerates Aβ aggregation in vitro, and the Abstract describes APOE4–Aβ1-40 co-aggregation in rats. Neither passage establishes direct interaction with both soluble and fibrillar Aβ. The deposition clause has a separate citation in the printed sentence and is not assessed here. (LLM, conf=0.78)
Experimental — accuracy not yet measuredApoE4 induces excessive Ca2+ levels and neuronal death.
“this ApoE isoform also induces excessive Ca2+ levels and neuronal death [38]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [38]
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Cites
HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?
Simões-Pires, C., Zwick, V., Nurisso, A., Schenker, E., Carrupt, P.-A., & Cuendet, M. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-7 · Cited by 341 · see citing works
Alzheimer's Disease Mechanisms and Emerging Roads to Novel Therapeutics
Sala Frigerio, C., & De Strooper, B. (2016) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-070815-014015 · Cited by 116 · see citing works
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Research works printed but not linked: 2
- national research council (uS) institute for laboratory animal research: Guide for the care and use of laboratory animals. national academies Press, Washington, dc, 1996.
- Paxinos G and Watson c: The rat Brain in Stereotaxic coordinates. 6th edition. Hard cover edition, academic Press, San diego, ca, 2007.
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Pires, M., & Rego, A. C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010778 · Cited by 157 · see citing works
- Authors
- Ding, Y., Kang, A., Tang, Q., & Zhao, Y.
- Affiliations
- Yuhuangding Hospital (CN)
- Venue
- Molecular Medicine Reports
- Publisher
- Spandidos Publications
- Published
- 2019-08-08
- Volume
- 20
- Issue
- 4
- Pages
- 3363-3370
- ISSN
- 1791-2997 (ISSN-L)
- 1791-3004
- OpenAlex
- W2967588325
- Cited by
- 7
- References
- 2
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 3 · 2021: 1
- FWCI
- 0.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Medicine Reports (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- HDAC6, APOE ε4, Aβ40, Alzheimer's disease, brain injury, hippocampus, choline acetyltransferase, tau protein, glycogen synthase kinase-3β, tau phosphorylation, neuroprotection
- MeSH terms
- Histone Deacetylase 6, Animals, Brain Injuries, Choline O-Acetyltransferase, Hippocampus, Male, Peptide Fragments, Gene Expression Regulation, Enzymologic, Amyloid beta-Peptides, tau Proteins, Rats, Sprague-Dawley, Maze Learning, Rats, Apolipoprotein E4, Histone Deacetylase Inhibitors, Spatial Memory, Protein Aggregation, Pathological
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