Translational control by eIF2α phosphorylation and its downstream effectors in AD brains and in primary microglia exposed to Aβ or tau oligomers
Bibliographic record
Abstract
BACKGROUND: The major histopathological hallmarks of Alzheimer's disease (AD) are neurofibrillary tangles, composed of the tau protein, and fibrillar aggregates of Aβ peptide. Considerable evidence points to important roles for soluble Aβ oligomers (AβOs) and, more recently, tau oligomers (TauOs) in the pathogenesis of AD. We and others have demonstrated that Aβ and tau aggregates impair neuronal mRNA translation (protein synthesis) through inhibitory phosphorylation of the eukaryotic initiation factor 2 α (eIF2α-P), and that this leads to cognitive impairment in AD. Microglia play an essential role in innate immune response, and in clearance of neurotoxins from the brain. Aberrant microglial activation is thought to represent an important causative factor in AD pathogenesis. Even though several cellular events underlying AD pathophysiology are well established, little is known on the mechanisms underlying loss of microglial homeostasis. Specifically, the regulation of microglial protein synthesis in AD remains elusive. METHODS: In this work, we analyzed the regulation of protein synthesis in postmortem AD brains, and then specifically in primary microglia cultures exposed to AβOs or TauOs. RESULTS: eIF2α-P is increased and associated with both CERAD and Braak stages in the AD prefrontal cortex. eiF2a-P is further associated with CERAD, but not with Braak stages, in the AD hippocampus, suggesting that Aβ and tau aggregates differentially affect eIF2α-P in distinct brain anatomical regions. In cortical primary microglia cultures, neither AβOs nor TauOs changed eIF2α-P levels, its downstream effector ATF4, or global protein synthesis rates at 6 or 24 h post-exposure. Despite the absence of changes in these mechanisms, AβOs induced an increase in the levels of fractalkine receptor CX3CR1, and a trend of increase in high mobility group box-1 (HMGB1) protein at 24 h of treatment. CONCLUSIONS: Our findings indicate that eIF2α-P and its downstream signaling are not changed in microglia exposed to AβOs or TauOs. Future work is warranted to explore other mechanisms underlying mRNA translation in AD microglia.
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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 | 0.000 | 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".