Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice
Bibliographic record
Abstract
ABSTRACT Microglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimer’s disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNA in situ hybridization and immunohistochemistry, we demonstrate that endogenous Tyrobp transcription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with either APP/PSEN1 or MAPT P301S mice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the latter. Apolipoprotein E ( Apoe ) transcription was upregulated in MAPT P301S mice overexpressing TYROBP and transcription of genes previously associated with Apoe , including Axl , Ccl2 , Tgfβ and Il6 , was altered in both APP/PSEN1 and MAPT P301S mice overexpressing TYROBP. Lastly, Tyrobp and Apoe mRNAs were clearly increased in Trem2 -null mice in microglia recruited around a cortical stab injury or amyloid-β (Aβ) deposits. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent. Our results provide compelling evidence that TYROBP-APOE signaling in the microglial sensome does not require TREM2. We propose that activation of a TREM2-independent TYROBP-APOE signaling could be an early or even initiating step in the transformation of microglia from the homeostatic phenotype to the Disease-Associated Microglia (DAM) phenotype.
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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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".