Phosphorylated tau interactome in the human Alzheimer’s disease brain
Bibliographic record
Abstract
Abstract Background Accumulation of phosphorylated tau (pTau) is a key pathological feature of Alzheimer’s disease (AD). pTau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles (NFTs). The pathological actions of pTau are mediated by surrounding neuronal proteins, however our knowledge of the specific proteins that pTau interacts with in AD is surprisingly limited. Therefore, we used two complementary proteomics approaches to map the pTau interactome for the first time. Method We performed quantitative proteomics on NFTs microdissected from patients with advanced AD. Second, we used affinity purification‐mass spectrometry (AP‐MS) to pinpoint which of the proteins identified directly interacted with pTau. Specific proteins of interest were validated using targeted co‐immunoprecipitation (co‐IP) and immunohistochemistry (IHC). Result 542 proteins were identified in NFTs including the detection of many proteins known to be present in NFTs (e.g. MAPT, UBB and APOE). AP‐MS confirmed that 75 proteins present in NFTs directly interacted with pTau. 54 of these proteins have been previously associated with tau, therefore validating our proteomic approach. More importantly, 15 of these proteins were previously known to be associated with AD, but not directly linked to tau (e.g. VAMP2, HNRNPA1). Network analysis showed that the pTau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation, and we were able to pinpoint specific proteins that pTau interacts with in these pathways. Importantly, we also identified six novel proteins, not previously known to be associated with pTau or AD. Among these, Secernin‐1 (SCRN1) was selected for validation. Co‐IP of SCRN1 confirmed its interaction with pTau in AD brains, and IHC showed that SCRN1 was uniquely associated with pTau pathology in AD and not in other neurodegenerative diseases such as Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration. Conclusion Combined, our results provide a roadmap for future studies examining the pathological effects of pTau and for identifying possible new drug targets and biomarkers such as SCRN1 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 | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".