Examining the Role of <i>SORL1</i> in Driving Alzheimer's Disease‐Related Alterations in Endolysosomal Trafficking in Neurons and Microglia
Bibliographic record
Abstract
Abstract Background Disruption of endolysosomal trafficking is a key pathogenic driver in Alzheimer's disease (AD). Among the genes linked to the endosomal pathway in AD, SORL1 is recognized as one of the most significant risk factors. SORL1 encodes an endocytic sorting receptor that regulates endosomal trafficking and processing of crucial AD‐related molecules, including pathogenic forms of amyloid‐β (e.g., Aβ42) and amyloid precursor protein (APP). Using complementary cell‐based models, we examined the impact of a protein‐truncating variant of SORL1 on endolysosomal trafficking and APP processing. Method Induced pluripotent stem cell (iPSC) lines were generated from two siblings with early‐onset AD carrying a rare protein‐truncating deletion in SORL1 (rs1343336951; p.C1431fs). SORL1 wild‐type isogenic control iPSC lines were created using CRISPR/Cas9 from these patient‐derived lines. Following validation, the iPSCs were differentiated into forebrain neurons and microglia to assess the impact of the SORL1 deletion on endolysosomal trafficking in each cell‐type. Additional analyses were performed in HEK293‐APPswe cells overexpressing either wild‐type SORL1 or the C1431fs variant. Result In HEK293‐APPswe cells, the C1431fs variant enhanced secretion of Aβ42 ( p <0.01), Aβ40 ( p <0.01), as well as soluble α‐secretase (sAPPα; p <0.01) and β‐secretase (sAPPβ; p <0.01) cleavage products. Furthermore, C1431fs led to an increase in the secretion of soluble SORL1 ( p <0.01). Surface biotinylation experiments showed that C1431fs reduced levels of SORL1 at the cell surface ( p <0.05), while increasing the surface levels of APP ( p <0.05). In SORL1 +/C1431fs neurons, we observe an accumulation of APP in early endosomes ( p = 0.002), endosomal swelling ( p = 0.004), and a higher number of early endosomes per cell ( p = 0.018). Additionally, SORL1 +/C1431fs neurons trend toward increased secretion of Aβ42 compared to controls. Our analysis of phagocytosis in SORL1 +/C1431fs microglia, assessed by the uptake of pHrodo‐labeled fibrillar Aβ42, suggests that the deletion reduces phagocytic activity. Current investigations in microglia are evaluating the concentration of specific cytokines and chemokines secreted in response to proinflammatory stimuli. Conclusion Our findings suggest that the SORL1 C1431fs deletion is capable of inducing defects in endolysosomal trafficking in both neurons and microglia. Ongoing studies in SORL1 +/C1431fs microglia and neurons will further expand our understanding of SORL1's role in regulating endolysosomal phenotypes across multiple cell types implicated in AD.
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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 | 0.001 | 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".