Loss of Complement Factor D suppresses alternative pathway activation but fails to reduce lipofuscin accumulation in the retinal pigmented epithelium of <i> Abca4 <sup>-/-</sup> </i> mice
Bibliographic record
Abstract
Abstract Stargardt disease (STGD1) is the most common inherited macular dystrophy, caused by loss-of-function mutations in ABCA4 that result in bisretinoid-containing lipofuscin accumulation in the retinal pigment epithelium (RPE), and progressive photoreceptor degeneration. Oxidative stress and complement system activation have been implicated as contributors to disease pathogenesis, but the requirement for alternative pathway activation in STGD1 remains unclear. To directly assess this, we used a genetic approach to generate pigmented mice deficient for both Abca4 and Cfd , an essential serine protease for alternative pathway initiation and amplification. Complement protein analysis revealed increased total C3 immunolabeling in the RPE and choroid of Cfd -/- mice, while C3d deposition at the RPE basal labyrinth and apical microvilli was markedly reduced, consistent with impaired alternative pathway activity. Western blotting confirmed altered C3 fragment profiles in Cfd -/- backgrounds, supporting a constitutive role for the alternative pathway in RPE complement activation. However, loss of Cfd did not prevent lipofuscin accumulation in the RPE of Abca4 -/- mice. Under light-induced stress, we unexpectedly observed a modest attenuation of outer nuclear layer thinning in Abca4 -/- that was unchanged by Cfd loss, which independently also showed a comparable rescuing effect. Together, these findings demonstrate that while the alternative pathway is a major driver of complement activation in the RPE and contributes only modestly to photoreceptor degeneration under light stress, its inhibition is insufficient to alter lipofuscin accumulation in pigmented Abca4 -/- mice.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".