O3‐07‐02: Bradykinin B1 receptor blockade in the treatment of Alzheimer's disease: improvement of cognitive and cerebrovascular functions and reduction of amyloidosis
Bibliographic record
Abstract
Alzheimer's disease (AD) is characterized not only by a cerebrovascular pathology, amyloidosis and cognitive deficits, but also by neuroinflammation that involves the kallikrein-kinin system. Strong evidence suggests that Bradykinin (BK) and its inducible receptor B1 (B1r) may be involved in AD. Previous experiments showed that the memory deficits triggered by intracerebral injection of beta-amyloid (Ab) could be reduced by blockade of B1r. We propose that B1r are induced in the brain of AD patients and that they contribute to the development of the disease. To test our hypothesis, we used adult transgenic mice (APPSwe, Ind; J20 line) that display several salient features of AD. We studied by immunocytochemistry the distribution of B1r in brain and its association with Ab deposits and activated glia. We then attempted to reverse the cognitive and vascular deficits with the brain-penetrant B1r antagonist SSR240612 (10 mg/kg/day, 5 and 10 weeks). Learning and memory were tested in the Morris water maze. Cerebral blood flow (CBF) response evoked by whisker stimulation was monitored by laser Doppler flowmetry. Vasomotor responses were evaluated on isolated pressurized segments of middle cerebral artery using online videomicroscopy. Amyloid plaques burden and tissue levels of Ab were measured using Thioflavin-S staining, anti-Ab immunolabelling and ELISA. B1r appeared increased in APP mice, particularly in the hippocampus, where double immunostaining showed its expression by activated astrocytes (GFAP), but not microglia (CD11b), surrounding Ab deposits. Learning and memory were significantly improved after 5 and 10 weeks of SSR240612 treatment. These treatments also ameliorated evoked CBF responses. Both treatments completely rescued dilations to acetylcholine. In treated wild-type (WT) mice, however, contractions induced by endothelin-1 and NO synthesis inhibition were significantly reduced compared to untreated WT. BK elicited a biphasic response (contraction followed by relaxation) in all groups, with a tendency to constrict and dilate more in APP and treated WT mice, respectively. Finally, soluble Ab1-42 levels and Ab plaque load were significantly reduced in the brain of APP mice after both treatments. Together, these data support a role of the kallikrein-kinin system in the pathogenesis of AD, and suggest that it may represent a new therapeutic target.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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".