Neuroinflammation in Alzheimer's Disease: a therapeutic target
Bibliographic record
Abstract
Alzheimer's disease (AD), the most common dementia, is an age-related neurodegenerative disorder characterized by memory loss, extracellular β-amyloid (Aβ) peptide deposits and intracellular neurofibrillary tangle formation. Current animal models of AD center on the precipitating role of Aβ deposition in a cascade of biological events that ultimately lead to neurodegeneration and dementia. However, increasing evidence shows that the amount of measurable amyloid deposition is a relatively weak correlate of cognitive function impairment among AD patients or individuals at risk for AD. Furthermore, autopsy studies reveal that older individuals with significantly elevated amyloid levels have no symptoms of AD. Together, these findings suggest that Aβ is necessary but perhaps not sufficient to cause the AD syndrome. Neuroinflammation has been implicated in cognitive aging for years. Neuroinflammatory response consists of activated microglia and astrocytes and the release of proinflammatory markers. Acute inflammation plays a critical role in brain function against insults. Neuropathological and neuroimaging studies have demonstrated that uncontrolled glial activation and neuroinflammation in the AD brain may contribute independently to neural dysfunction and cell death. This thesis shows that both microglial and astroglial activation occurred in paralleled with the pattern of learning deficits rather than amyloid pathology in an APP/PS1 transgenic mouse model of AD. These findings suggest that neuroinflammation might directly contribute to the development and progression of cognitive deficits in APP/PS1 mice. In the context of significant amyloid deposition, the results of the current study suggest that mechanisms underlying the inflammatory process might be an important therapeutic target for AD. Finally, this work presents a chronic administration of quetiapine in APP/PS1 transgenic mice resulted in a marked change in microglial and astrocyte activation, proinflammatory cytokine levels, and an improvement in behavioural performance. The beneficial effects of quetiapine occurred when there were only marginal changes in levels of total Aβ, suggesting the anti-inflammatory effect of quetiapine could account for the cognitive improvement observed in APP/PS1 transgenic mice. Moreover, we confirmed that quetiapine significantly reduced Aβ1-42 induced secretion of proinflammatory cytokines in primary cultured microglia. Both in vitro and in vivo experiments demonstrated that quetiapine ameliorated proinflammatory cytokine increases via suppression of NF-κB pathway activation. Since risk factors for the development of inflammation are modifiable, these findings suggest intervention and prevention strategies for the clinical syndrome of 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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".