PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke
Bibliographic record
Abstract
The proprotein convertase PCSK9 ( 1 ) is the third gene involved in autosomal dominant familial hypercholesterolemia ( Gain-of-function PCSK9 mutations result in increased levels of plasma low density lipoprotein (LDL) cholesterol ( 2-4 ). In contrast, gene disruption ( 5, 6 ) and loss-of-function mutations in PCSK9 ( 3, 7 ) prevent the degradation of the LDL receptor (LDLR), resulting in a higher clearance of plasma LDL-cholesterol. These seminal fi ndings led to the development of therapies based on PCSK9 inhibition/silencing for the treatment of hypercholesterolemia ( 8, 9 ). Although liver LDLR protein levels are reduced in mice injected with PCSK9 ( 10, 11 ) or overexpressing PCSK9 in hepatocytes ( 6 ), high quantities of PCSK9 can also downregulate LDLR protein levels in extrahepatic tissues such as the lung, adipose, and kidney ( 12, 13 ), suggesting that endogenous circulating PCSK9 that originates from hepatocytes ( 6, 13 ) may downregulate LDLR protein in others tissues. At adulthood, PCSK9 is highly expressed in liver and is also abundant in the small intestine, as well as in the kidney and brain throughout embryonic development ( 1 ). In mouse brain, PCSK9 is transiently expressed in the telencephalon [maximal at embryonic day (E)12.5] and cerebellum [from E17.5 to postnatal day (P)19] ( 1 ). At adulthood, it is only significantly expressed in the rostral extension of the olfactory peduncle (RE-OP) ( 1 ). In addition, transgenic mice Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role in cholesterol homeostasis through enhanced degradation of the LDL receptor (LDLR) in liver. As novel inhibitors/silencers of PCSK9 are now being tested in clinical trials to treat hypercholesterolemia, it is crucial to defi ne the physiological consequences of the lack of PCSK9 in various organs. LDLR regulation by PCSK9 has not been extensively described during mouse brain development and injury. Herein, we show that PCSK9 and LDLR are co-expressed in mouse brain during development and at adulthood. Although the protein levels of LDLR and apolipoprotein E (apoE) in the adult brain of Pcsk9 / mice are similar to those of wild-type (WT) mice, LDLR levels increased and were accompanied by a reduction of apoE levels during development. This suggests that the upregulation of LDLR protein levels in Pcsk9 / mice enhances apoE degradation. Upon ischemic stroke, PCSK9 was expressed in the dentate gyrus between 24 h and 72 h following brain reperfusion. Although mouse behavior and lesion volume were similar, LDLR protein levels dropped 2-fold less in the Pcsk9 / -lesioned hippocampus, without affecting apoE levels and neurogenesis. Thus, PCSK9 downregulates LDLR levels during brain development and following transient ischemic stroke in adult mice. -
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How this classification was reachedexpand
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 | 0.006 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".