Therapeutic potential of nuclear receptor agonists in Alzheimer's disease
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Bibliographic record
Abstract
central role and subsequently drives the dysregulation of the cytoskeletal protein, tau. The amyloid hypothesis is supported by a substantial body of scientific and clinical evidence (2). AD is typified by the progressive A deposition in the brain parenchyma as both diffuse and dense-core plaques, starting in isocortical areas, followed by limbic and allocortical structures, and finally subcortical structures (3). A peptide is generated by sequential cleavage of the amyloid precursor protein (APP) by the and secretases, yielding a heterogeneous pool of A species with different lengths, most prominently those of 40 or 42 amino acids in length. The A(1-42) species is more hydrophobic and highly self-aggregating, and is the principal species that is initially deposited in the brain of AD patients. APP can also be processed in a nonamyloidogenic pathway mediated by -secretase activity, generating a soluble APP fragment (sAPP), which is considered to have beneficial effects on neurons (4, 5). Genetically inherited familial forms of AD are caused by mutations in APP or in -secretase that favor A(1-42) generation, followed by aggregation and deposition. On the other hand, patients with "sporadic" late-onset AD, exhibit an impairment of A clearance from the brain, likely underlying the pathological A accumulation observed in this type of patient (6, 7). Thus, perturbation of A homeostasis caused by either increased production (familial AD) or impaired clearance (sporadic late-onset AD) of A peptides leads to the pathological accumulation of this peptide in the form of toxic A oligomers, disrupting synaptic function and plasticity, which is postulated to underlie the cognitive deficits observed in this disease. The deposition of A in the form of plaques results in neuritic Abstract Alzheimer's disease (AD) is characterized by an extensive accumulation of amyloid- (A) peptide, which triggers a set of deleterious processes, including synaptic dysfunction, inflammation, and neuronal injury, leading to neuronal loss and cognitive impairment. A large body of evidence supports that nuclear receptor (NR) activation could be a promising therapeutic approach for AD. NRs are ligandactivated transcription factors that regulate gene expression and have cell type-specific effects. In this review, we discuss the mechanisms that underlie the beneficial effects of NRs in AD. Moreover, we summarize studies reported in the last 10-15 years and their major outcomes arising from the pharmacological targeting of NRs in AD animal models. The dissection of the pathways regulated by NRs in the context of AD is of importance in identifying novel and effective therapeutic strategies.-Moutinho, M.
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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 | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.002 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| 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 it