<i>CHRFAM7A</i> overexpression in human iPSC-derived Interneurons dysregulates α7- nAChR surface expression and alters response to oligomeric β-amyloid peptide
Bibliographic record
Abstract
Abstract The α7 neuronal nicotinic receptor (α7-nAChR) gene, CHRNA7 , is widely expressed within the brain and at the periphery. It plays various important roles in cognition and immune functions. Decreased expression of α7-nAChR has been associated with Alzheimer’s disease (AD) triggered by the accumulation of the 42-amino acid beta-amyloid peptide (Aβ 1-42 ). The interactions of this peptide with α7-nAChR may represent a pivotal mechanism that is involved in pathogenesis of AD. The regulation of CHRNA7 is a complex process. Normal function of α7-nAChR in mammalian cells requires the co-expression of chaperone proteins such as RIC3 and NACHO which facilitate the formation of cell surface receptors. In humans, CHRNA7 regulation also involves the specific chimeric CHRFAM7A gene product dupα7, which may assemble with α7 subunits and lead to dominant negative regulation of α7-nAChR function. To further elucidate the complex interplay between CHRFAM7A gene product (dupα7), α7-nAChRs and Aβ 1-42 , we used human induced pluripotent stem cells (iPSC)-derived interneurons (INs). Four iPSC lines were analyzed for the presence of CHRFAM7A copies. Among them, a cell line with a null genotype was selected for the lentiviral overexpression of CHRFAM7A . Our data show that overexpression of CHRFAM7A led to a reduction in the surface detection of α7-nAChR ligand binding sites in iPSC-derived INs. INs expressing the α7-dupα7 subunit (α7-dupα7-INs) exhibited lower levels of RIC3 and NACHO. Upon agonist treatment by nicotine, an up-regulation of α7-nAChR ligand binding sites was observed in α7-dupα7-INs as compared to non-transduced INs (α7-INs). At low levels of Aβ treatment, α7-INs displayed a significant reduction in production of reactive oxygen species (ROS), while high levels resulted in a slight increase. In contrast, α7-dupα7-INs exhibited lower baseline levels of ROS that remained unaltered by Aβ treatment. ROS are known to exacerbate AD pathogenesis. We hypothesize that such effects may also be triggered by α7-dupα7-INs in the brain of patients. Further investigations are currently undertaken to confirm this hypothesis.
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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) | 0.000 | 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) | 0.002 | 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".