[O2–04–01]: CLEARANCE OF BETA‐AMYLOID IS FACILITATED BY APOLIPOPROTEIN E AND CIRCULATING HIGH‐DENSITY LIPOPROTEINS IN BIOENGINEERED HUMAN VESSELS
Bibliographic record
Abstract
In the last decade, the complex interrelationship between cerebrovascular dysfunction and AD is increasingly appreciated. Established vascular risk factors for AD include hypertension, dyslipidemia, and type II diabetes, exacerbate cognitive decline and cerebral small vessel diseases, including cerebral amyloid angiopathy (CAA) and microvascular degeneration, are comorbidities in 60–90% of AD autopsy cases. Interestingly whereas high-density lipoproteins (HDL) plasma level positively correlates with cognitive function in AD patients, its effects on human cerebrovascular integrity remain poorly understood. In the present study we developed a novel human based in vitromodel of the vasculature to study the role of HDL on the cerebrovascular function in the context of AD. Primary human endothelial (EC) and smooth muscle cells (SMC) were cultivated in the absence (bipartite) or presence (tripartite) of human astrocytes (apoE3/E3) using a scaffold-directed dynamic, pulsatile flow bioreactor system. Histological analysis demonstrated the formation of a dense tissue composed of a tight layer of ECs in the lumen and several layers of SMCs for the bipartite tissue and several layers of astrocytes on the ablumen for the tripartite mimicing the structure of pial, leptomeningial and penetrating cerebral arteries. We have injected Aߠdirectly into the tissue chamber to mimic amyloid coming from the brain side of the vessel. To further analyze the role of lipoproteins on vascular amyloid accumulation we circulated HDL isolated form healthy young individuals in the lumen and/or added apoE with Aß. Histological staining and ELISA quantifications confirmed the accumulation of Aߠwithin our vessel equivalent time and dose dependently. We further show that lipoproteins on both sides of the vessel synergize to facilitate Aߠtransport across the human cerebral vessel. Importantly, our data also show that lipoproteins facilitate Aß42 transport more efficiently than Aß40, which is consistent with human data showing that Aß40 is the primary species that accumulates in CAA. Moreover, apoE4 is less effective than apoE2 in promoting Aߠtransport, which is also consistent with the well-established role of apoE4 in Aߠdeposition in AD. Taken together, our results establish the utility of human engineered cerebral vessels as a highly innovative in vitro platform to study key mechanistic questions relevant to 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 | 0.000 | 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) | 0.002 | 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".