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PINK1-dependent NFKB signaling contributes to amyloid pathology in Alzheimer disease
Fang Ling Du, Qing Yu, Gang Hu, Chyuan‐Sheng Lin, Shirley ShiDu Yan. Autophagy, 2025-05-04
Topic: Brain proteins, microglia and lab models
Mitochondrial dysfunction plays a preponderant role in the development of Alzheimer disease (AD). We have demonstrated that activation of PINK1 (PTEN induced kinase 1)-dependent mitophagy ameliorates amyloid pathology, attenuates mitochondrial and synaptic dysfunction, and improves cognitive function. However, the underlying mechanisms remain largely unknown. Using a newly generated PINK1-AD transgenic mouse model and AD neuronal cell lines, we provide substantial evidence supporting the contribution of PINK1-mediated mitochondrial ROS (reactive oxygen species) and NFKB/NF-κB (nuclear factor kappa B) signaling to altering APP (amyloid beta precursor protein) processing and Aβ metabolism. Enhancing neuronal PINK1 is sufficient to suppress Aβ-induced activation of NFKB signal transduction in PINK1-overexpressed Aβ-AD mice and Aβ-producing neurons. Blocking PINK1-mediated NFKB activation inhibits activities of BACE1 (beta-secretase 1) and γ-secretase, which are key enzymes for cleavage of APP processing to produce Aβ. Conversely, loss or knockdown of PINK1 produces excessive ROS, along with increased phosphorylated NFKB1/p50 and RELA/p65 subunits, APP-related BACE1 and γ-secretase, and Aβ accumulation. Importantly, these detrimental effects were robustly blocked by the addition of scavenging PINK1 Aβ-induced mitochondrial ROS, leading to the suppression of NFKB activation, restoration of normal APP processing, and limitation of Aβ accumulation. Thus, our findings highlight a novel mechanism underlying PINK1-mediated modulation of Aβ metabolism via a ROS-NFKB-APP processing nexus. Activation of PINK1 signaling could be a potential therapeutic avenue for the early stages of AD by combining improving mitochondrial quality control with limiting amyloid pathology in AD.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Du, F. L., Yu, Q., Hu, G., Lin, C., & Yan, S. S. (2025). PINK1-dependent NFKB signaling contributes to amyloid pathology in Alzheimer disease. Autophagy. https://doi.org/10.1080/15548627.2025.2463322
Vancouver
Du FL, Yu Q, Hu G, Lin C, Yan SS. PINK1-dependent NFKB signaling contributes to amyloid pathology in Alzheimer disease. Autophagy. 2025. doi:10.1080/15548627.2025.2463322. PMID: 40320714.
BibTeX
@article{du2025-40320714,
author = {Du, Fang Ling and Yu, Qing and Hu, Gang and Lin, Chyuan‐Sheng and Yan, Shirley ShiDu},
title = {{PINK1-dependent NFKB signaling contributes to amyloid pathology in Alzheimer disease}},
journal = {Autophagy},
year = {2025},
doi = {10.1080/15548627.2025.2463322},
pmid = {40320714},
url = {https://doi.org/10.1080/15548627.2025.2463322}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
Key findings
- We have demonstrated that activation of PINK1 (PTEN induced kinase 1)-dependent mitophagy ameliorates amyloid pathology, attenuates mitochondrial and synaptic dysfunction, and improves cognitive function.
- Thus, our findings highlight a novel mechanism underlying PINK1-mediated modulation of Aβ metabolism via a ROS-NFKB-APP processing nexus.
Why it matters
In a PINK1-AD transgenic mouse model and AD neuronal cell lines, PINK1-mediated mitochondrial ROS and NFKB signaling affected APP processing and Aβ metabolism. This is animal and cell research into a mechanism, not a treatment or prevention for people.
Study details
- Evidence strengthLow
How this study scored 42/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Autophagy) |
| Journal's citation record | 2 / 4 | Autophagy: journal h-index 240 (OpenAlex, 2026-10-29) |
| 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 | 4 / 5 | 2025 — within 3 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 | 2 / 7 | Cited 10 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 5.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 10 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Shirley ShiDu Yan: h-index 52 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Columbia University: institution h-index 1,824 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40320714) |
| Free to read | 2 / 2 | Free to read |
| Total | 42 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1080/15548627.2025.2463322
- PubMed: 40320714
- Original source →
- Free full text: PubMed Central →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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