P4‐182: Inhibition of ABCG2 transport function by amyloid‐beta peptide augments cellular oxidative stress and inflammatory gene expression in cells
Bibliographic record
Abstract
Alzheimer 's disease (AD) is characterized by accumulation and deposition of Aβ peptides in brain. Aβ binds heme forming a complex with peroxidase activities that generates increased levels of non-heme iron. Liable iron causes ROS activation, transcription of oxidant dependent genes and increased APP. ABCG2 is a membrane efflux transporter that regulates cellular heme and porphyrin levels. ABCG2 is induced during hypoxic stress as a protective mechanism to regulate toxic levels of cellular porphyrin and protect the brain from toxic substrate accumulation. This study examines the role of ABCG2 in the regulation of Aβ-induced oxidative stress and inflammatory gene expression. ABCG2 was transfected into HEK293 cells followed by drug uptake assays or H202/TBHP treatment in the presence or absence of Aβ. Conditioned media were prepared from human microglia treated with Aβ1–42/40 and applied to immortalized human brain endothelial cells (iHBEC). RNA/protein was isolated from tissues/cells for RT-PCR/Q-PCR and Western blot. Cell toxicity was assessed by PI assay. ROS was assayed using a ROS-oxidized fluorescent substrate measured on a plate reader or imaged by fluorescent microscopy. ABCG2 is up-regulated in human AD/CAA brain and in iHBEC exposed to microglial-conditioned media (MCM). Aβ was shown by co-immunoprecipation to bind ABCG2. ABCG2 efflux of rhodamine was impaired in the presence of Aβ1–40. ROS was induced in HEK293 cells by H2O2 or TBHP treatment. Aβ1–40 treatment combined with H2O2 or TBHP synergistically increased ROS production. ABCG2 expression inhibited H202/TBHP-induced ROS and decreased cell toxicity but did not reduce ROS accumulation induced by Aβ with H2O2 or TBHP. Inflammatory gene expression was increased in H2O2-or TBHP-treated HEK293 cells and in iHBEC cells treated with MCM. ABCG2 reduced H2O2/TBHP-induced expression of inflammatory genes but not in the presence of Aβ. These results suggest that ABCG2 plays a protective role during oxidative stress by maintaining possibly heme/porphyrin levels and reducing inflammatory gene response. Aβ inhibits ABCG2 transport function which augments oxidative stress and inflammatory gene expression. Increased amyloid burden causing transport/clearance restriction and oxidative stress combined with the vulnerability of an aging brain may lead to a synergistic progression of Alzheimer's pathology.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".