P4–430: Antisense oligonucleotide‐mediated inhibition of miR‐33 in cultured neurons, astrocytes and microglia: Effects on ABCA1 expression, APOE lipidation, cellular cholesterol and beta‐amyloid neurotoxicity
Bibliographic record
Abstract
Increasing the expression of ATP-binding cassette transporter A1 (ABCA1) reduces plaque deposits and improves memory performance in mouse models of Alzheimer's disease (AD). This has predominantly been attributed to ABCA1-mediated lipidation of apolipoprotein E (apoE) in the brain and facilitating amyloid clearance. Despite the beneficial effects of LXR agonists - therapeutic compounds that increase ABCA1 expression- in preclinical studies, their utility for the treatment of AD is limited by serious side effects underscoring the need for discovering alternative therapeutic approaches. MicroRNAs (miRNAs) are endogenous small, noncoding RNA molecules that bind to target mRNAs leading to translational repression. MicroRNA-33 (miR-33) regulates the expression of key genes involved in cellular cholesterol metabolism including ABCA1 and has emerged as a promising target in experimental models of atherosclerosis and diabetes. The objective of this study is to evaluate the effects of increasing ABCA1 in brain cells by inhibiting miR-33 and study the cellular and molecular mechanisms relevant to AD pathogenesis. Antisense oligonucleotides (ASOs), primary neurons, astrocytes and microglia, western immunoblotting, cellular cholesterol, cholesterol efflux, phagocytosis and cytokine release assays, neuronal viability assays, intracerebroventricular infusion, APP/PS1 mice and mouse neuropathology. Treatment of cultured neurons, astrocytes and microglia with an ASO targeting miR-33 increases ABCA1 expression in a concentration dependant manner. This is accompanied by increased cholesterol and ApoE efflux by astrocytes into the cultured medium. Interestingly, increasing ABCA1 expression did not change the total cellular cholesterol content in neurons and astrocytes, neither did it protect neurons against Aβ toxicity. Moreover, i.c.v. infusion of miR-33 ASO also increased hippocampal and striatal ABCA1 expression in wild type mice. We demonstrate that ASO mediated inhibition of miR-33 can successfully be employed towards increasing ABCA1 expression in cultured brain cells and in vivo. Our data suggest that increasing ABCA1 expression enhances cholesterol and ApoE efflux, which may indirectly promote amyloid clearance. It remains to be determined whether miR-33 inhibition affects APP processing or has any beneficial effects on the development and progression of AD like neuropathology in relevant animal models. We are confident that these findings will have significant impact on the development of novel therapies for 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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 | 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".