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Mechanistic study of PHLDA1 in cognitive dysfunction of Alzheimer’s disease model mice via FoxO1‑mediated neuroinflammation
Liu X, Liu Z, Lv Z, Lei Y, Zhou Z, Xu Z, Duan J, Xing W et al.. Research Square, 2026-10-12
Topic: Inflammation, microglia and astrocytes
Neuroinflammation is a core driver of Alzheimer’s disease (AD) progression. Pleckstrin homology-like domain family A member 1 (PHLDA1) is known to regulate Toll-like receptor-mediated immunity, but its role in AD-associated neuroinflammation remains unknown. Here we demonstrate that PHLDA1 suppresses FoxO1 phosphorylation and inactivation through a dual mechanism: it inhibits upstream AKT activation and competitively binds the 14-3-3 chaperone, thereby promoting FoxO1 nuclear retention and sustaining downstream TLR4-driven inflammatory transcription. In APP/PS1 mice, elevated PHLDA1 correlates with increased total FoxO1 but decreased phosphorylated FoxO1 (p-FoxO1), 14-3-3, and Akt, which collectively drive FoxO1 nuclear accumulation and persistent inflammatory signaling. Consequently, this triggers microglial overactivation, cascading release of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), an elevated Aβ42/Aβ40 ratio, and aggravated plaque deposition, ultimately leading to neuronal apoptosis and cognitive deficits. Notably, hippocampal knockdown of PHLDA1 using AAV-shRNA reverses these molecular, pathological, and behavioral abnormalities. Collectively, the PHLDA1–FoxO1–TLR4 axis may significantly influence AD neuroinflammation, and targeting PHLDA1 provides a rationale for developing anti-inflammatory therapeutic strategies against AD.
Key findings
- Collectively, the PHLDA1–FoxO1–TLR4 axis may significantly influence AD neuroinflammation, and targeting PHLDA1 provides a rationale for developing anti-inflammatory therapeutic strategies against AD.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on 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 and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| 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 | Laboratory or animal study (title names “mice”) — scores zero |
| 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Liu, X., Liu, Z., Lv, Z., Lei, Y., Zhou, Z., Xu, Z., et al. (2026). Mechanistic study of PHLDA1 in cognitive dysfunction of Alzheimer’s disease model mice via FoxO1‑mediated neuroinflammation. Research Square. https://doi.org/10.21203/rs.3.rs-10948741/v1
Vancouver
Liu X, Liu Z, Lv Z, Lei Y, Zhou Z, Xu Z, et al. Mechanistic study of PHLDA1 in cognitive dysfunction of Alzheimer’s disease model mice via FoxO1‑mediated neuroinflammation. Research Square. 2026. doi:10.21203/rs.3.rs-10948741/v1.
BibTeX
@article{liu2026-6e29bce4,
author = {Liu, X. and Liu, Z. and Lv, Z. and Lei, Y. and Zhou, Z. and Xu, Z. and Duan, J. and Xing, W. and others},
title = {{Mechanistic study of PHLDA1 in cognitive dysfunction of Alzheimer’s disease model mice via FoxO1‑mediated neuroinflammation}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-10948741/v1},
url = {https://doi.org/10.21203/rs.3.rs-10948741/v1}
}
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