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HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease
Jeongmi Lee, Yongeun Cho, Bo Youn Choi, Hark Kyun Kim, Yeongyeong Lee, Eunae Kim, Jihoon Han, Jae Hoon Sul et al.. Brain : a journal of neurology, 2026-03-06
Topic: Inflammation, microglia and astrocytes
Alzheimer's disease (AD) is marked by amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation. The β-site APP cleaving enzyme 1 (BACE1) is a key driver of Aβ production, while the NLRP3 inflammasome mediates microglial inflammatory responses. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase, is upregulated in AD, yet its role in disease mechanisms remains unclear. Here, we show that HDAC6 promotes BACE1 protein stability through direct deacetylation of its C-terminal lysine (K501), thereby increasing Aβ production. HDAC6 also facilitated NLRP3 inflammasome activation in microglia, increasing IL-1β production in a catalytic domain-dependent manner. HDAC6 deficiency in 5xFAD mice reduced BACE1 accumulation, Aβ deposition, ASC speck formation, and IL-1β levels, accompanied by improved cognitive performance. Transcriptomic profiling further revealed downregulation of disease-associated microglial and neurotoxic astrocyte signatures alongside enrichment of synaptic pathways. These findings establish HDAC6 as a dual regulator of Aβ production and neuroinflammation, highlighting it as a promising therapeutic target in AD.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Lee, J., Cho, Y., Choi, B. Y., Kim, H. K., Lee, Y., Kim, E., et al. (2026). HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease. Brain : a journal of neurology. https://doi.org/10.1093/brain/awag089
Vancouver
Lee J, Cho Y, Choi BY, Kim HK, Lee Y, Kim E, et al. HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease. Brain : a journal of neurology. 2026. doi:10.1093/brain/awag089. PMID: 41789727.
BibTeX
@article{lee2026-41789727,
author = {Lee, Jeongmi and Cho, Yongeun and Choi, Bo Youn and Kim, Hark Kyun and Lee, Yeongyeong and Kim, Eunae and Han, Jihoon and Sul, Jae Hoon and others},
title = {{HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease}},
journal = {Brain : a journal of neurology},
year = {2026},
doi = {10.1093/brain/awag089},
pmid = {41789727},
url = {https://doi.org/10.1093/brain/awag089}
}
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Key findings
- Transcriptomic profiling further revealed downregulation of disease-associated microglial and neurotoxic astrocyte signatures alongside enrichment of synaptic pathways.
- These findings establish HDAC6 as a dual regulator of Aβ production and neuroinflammation, highlighting it as a promising therapeutic target in AD.
Study details
- Evidence strengthLow
How this study scored 48/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 27 of the 56 points we could judge it on, which is 48 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41789727) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 27 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 27 of the 56 points we could judge it on is 48 out of 100. |
| Total | 48 / 100 | — |
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