Modulation of inflammatory mediators during aging and amyloid-beta pathology
Bibliographic record
Abstract
An elevation in the expression of inflammatory mediators has been reported in aging and Alzheimer's disease (AD). As chronic inflammation has been associated with toxicity, this thesis focused on strategies that could reduce the expression of inflammatory mediators in aging, and help understand the role(s) of these mediators in AD. A promising approach to reduce inflammation used the activation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). In chapter 4, oral or intracerebroventricular administration of the PPAR-gamma agonist, ciglitazone, potentiated IL-1beta and TNF-alpha expression in aging Fischer 344 (F344) rat brains. These results may be a consequence of the paradigm used, as F344 rats represent an 'unchallenged' naturally occurring aging model. In chapter 5, the expression of inflammatory mediators in AD, a neurodegenerative disease characterized by the aggregation of the amyloid-beta peptide (Abeta), was assessed using acute and chronic models of Abeta exposure as tools to study disease onset and progression, respectively. A single intracerebral injection of Abeta (acute model) in rats resulted in an increase in the expression of pro-inflammatory mediators, but not in TGF-beta1. In contrast, aging TgCRND8 mice (chronic model) revealed low levels of pro-inflammatory mediators, but increased levels of TGF-beta1 when compared to age-matched non-Tg mice. These results suggest that the increase in TGF-beta1 expression may require cumulative neuronal toxicity in addition to Abeta exposure. Intervention studies in AD including NSAID administration or genetic modulation in mouse models of AD highlight a role for inflammatory mediators as modulators of Abeta pathology. In chapter 6, the role of TGF-beta1 was evaluated through the administration of TGF-beta1 neutralizing antibodies for a 30-day period in TgCRND8 mice, which proved effective in reducing total soluble Abeta levels. Conclusion. This thesis showed that age-associated inflammation may not be repressed by the use of PPAR-gamma agonists. In addition, my results indicate that the expression of inflammatory mediators is regulated as a function of the duration of Abeta exposure. Finally, my findings showed for the first time that neutralization of one specific cytokine, without the use of genetic modifications, can alter Abeta pathology in a mouse model of AD.
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 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 | 0.000 |
| 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".