SA101. Characterization of Presynaptic SNAP-25 Aggregates in Human Postmortem Brain: A Novel Pathologic Index in Schizophrenia?
Bibliographic record
Abstract
Background: Deposition of misfolded protein aggregates is the pathological hallmark of various brain diseases. To date, no such pathological indices have been described in schizophrenia (SCZ). We previously identified abnormally enhanced SNARE (soluble NSF attachment protein receptor) complex assembly in SCZ postmortem brains [1], which could be associated with exacerbated presynaptic activity. Here, we explored the hypothesis that the biochemical stress upon presynaptic overstimulation might cause misfolding and aggregation of the SNARE proteins (SNAP-25, syntaxin-1, and VAMP). Methods: Postmortem orbitofrontal cortex (OFC) samples of 35 SCZ and 15 major depression (MDD) cases, and 28 healthy controls, were collected from either the Macedonian/New York State Psychiatric Institute Brain Collection or the Stanley Foundation Neuropathology Consortium. Aggregates were characterized by SDS-PAGE followed by immunoblotting, comparing mildly versus harshly denatured brain homogenates. Results: Using three different antibodies against SNAP-25, we identified various potential misfolded aggregates at ~50, ~75, and ~110 kDa. Antibodies against syntaxin-1 and VAMP did not recognize these bands and therefore were considered dimeric, trimeric, and tetrameric SNAP-25 aggregates, respectively. Other bands detected in syntaxin-1 and VAMP immunoblots were not consistently found with the different probing antibodies and were excluded from follow-up studies. Both dimeric and trimeric SNAP-25 aggregates were similarly expressed in the OFC of all diagnostic groups. In contrast, most control and MDD cases faintly expressed the SNAP-25 tetramer, whereas 21 of 35 SCZ cases showed a robust immunostaining. Thus, OFC tetrameric SNAP-25 levels were 7.2-fold (P < .0001) greater in SCZ compared to controls, while a nonsignificant reduction (–66%, P = .0761) was observed in MDD brains. ANCOVA tests confirmed the robust association between high tetrameric levels and SCZ (β = .56, P < .0001), while other potentially confounding factors (age, sex, postmortem interval, brain pH, and antipsychotic medication) had no influence on this SNAP-25 aggregate species. Regardless of diagnosis, subjects committing suicide displayed lower levels of the SNAP-25 tetramer (β = .34, P = .0004). Conclusion: These findings suggest that SNAP-25 tetrameric aggregates may represent a novel pathologic marker characterizing SCZ. Funding: The study was supported by CIHR Grants MT-14037 and MOP-81112. Reference 1. Ramos-Miguel et al., Biol Psychiatry 2015, 78: 361–373.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 | 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".