P3‐378: Misfolded superoxide dismutase 1 (SOD1) as a novel target for Alzheimer's disease
Bibliographic record
Abstract
As the world population ages, the incidence of Alzheimer's disease (AD) is predicted to increase significantly, and so will the need for “disease-attenuating” therapeutics. A particularly promising approach is immunotherapy to remove abnormal and/or toxic proteins. To date, this approach has been directed solely against monomeric amyloid beta (Aβ), rather than misfolded aggregated Aβ or other proteins, with limited success. Therefore, alternative targets need to be identified for the rational development of AD therapeutics. To this end, we have found that misfolded superoxide dismutase 1 (SOD1) co-localizes with amyloid plaques in AD brain. Misfolded and/or oxidized SOD1 is known to be important in the etiology of amyotrophic lateral sclerosis (ALS), and its presence in AD suggests similar pathological mechanisms may pertain. We and others have found that SOD1 can switch from a soluble free radical defence enzyme to a net generator of reactive oxygen/nitrogen species as it misfolds. We theorized that portions of the molecule (disease-specific epitopes; DSEs) would be newly exposed on the molecular surface of misfolded/aggregated SOD1, but inaccessible on the natively-structured protein. We have verified this approach by developing specific monoclonal antibodies directed against several DSEs. Using DSE mAbs, misfolded SOD1 is detectable by immunoprecipitation in the hippocampus and frontal cortex of human AD brains, but not in those of aged-matched controls; misfolded SOD1 also co-localizes within amyloid plaques in brain tissue from AD patients by immunofluorescence and immunohistochemistry. Similarly, misfolded SOD1 can be immunoprecipitated from the brains of APP/PS1 transgenic mice, a well-studied model for AD, as early as 6 months, but not in non-transgenic littermates. Misfolded SOD1 is also immunofluorescently detectable in whole mouse brain. Our results clearly demonstrate the presence of misfolded SOD1 in the brains of both transgenic APP/PS1 mice and human AD patients, suggesting it as a novel AD marker. We will examine AD brains for the presence of misfolded SOD1-derived free radicals and determine the level of SOD1 aggregation; both characteristics contribute to ALS pathogenesis and may be relevant in AD. In vivo studies to address the therapeutic potential of antibodies and vaccines to misfolded SOD1 are ongoing.
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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) | 0.004 | 0.002 |
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".