Immunodepletion of amyloid‐associated matrisomal proteins reduces Aβ in hiPSC‐derived neurons
Bibliographic record
Abstract
BACKGROUND: Large-scale unbiased proteomic profiling studies have identified a cluster of 31 proteins co-expressed with APP, which is termed the matrisome module 42 (M42). M42 is enriched in AD risk genes, including APOE, with mostly secreted proteins that bind heparin, collectively strongly correlate with the burden of brain pathology and cognitive trajectory, and localize to amyloid plaques in AD brain. For these reasons, M42 has been nominated as a novel therapeutic target for enabling drug discovery by our TREAT-AD Center. Here we immunodeplete several M42 proteins including MDK, SFRP1, HTRA1, QPRT, PTN, and SMOC1 using iPSC-derived neurons modeling autosomal dominant AD to investigate effects on amyloid production. METHOD: The AD-related APP Swedish mutation (APP KM670/671NL) was introduced into the well-characterized wildtype control iPSC line (WTC-11), and programming by the transcription factor neurogenin-2 (NGN2) was used to generate cultures of high purity excitatory neurons. Inhibition of a collection of M42 proteins with strong correlation with AD endophenotypes was performed by treating neurons with recombinant monoclonal antibodies. Western blot was used to confirm immunodepletion of the secreted protein targets, as well as to measure p-Tau and total Tau. Enzyme-linked immunosorbent assay (ELISA) kits specific for human Aβ40 and Aβ42 were used to quantify Aβ species. RESULT: Aβ40, Aβ42, p-Tau (AT8), p-Tau (S396), and total Tau, as well as ECM-associated proteins (MDK, SFRP1, HTRA1, QPRT, PTN, SMOC1) were elevated in neuronal media and cell lysate derived from hiPSCs carrying the APP Swedish mutation relative to WT controls. Immunodepletion of MDK, HTRA1, and PTN reduced Aβ species in neuronal media, while immunodepletion of QPRT increased Aβ species and SFRP1 showed no significant changes. CONCLUSION: hiPSCs with the APP Swedish mutation express and secrete increased levels of several M42 amyloid-associated proteins as in human AD. Reductions in Aβ species following immunodepletion of MDK, HTRA1, and PTN demonstrate the utility of hiPSC models for probing M42 function and therapeutic potential for 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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".