A putative role for PCSK9 in synaptic remodelling and plasticity in response to brain injury: implications for Alzheimer's disease
Bibliographic record
Abstract
Since the association of the ε4 allele of the apolipoprotein E (apoE) withAlzheimer's disease (AD) risk, growing evidences support a role for cholesterolmetabolism in the pathophysiology of this disease. Many genes involved in lipidmetabolism have now been studied and associate with the risk of AD. PCSK9 is aproprotein convertase recently identified as the third gene linked to familialhypercholesterolemia. It is a key regulator of plasma cholesterol concentrations byenhancing the degradation of cell surface low-density-lipoprotein receptor (LDLR). Thepresent project derives from the global hypothesis that in the brain, PCSK9 may play arole in cholesterol homeostasis by regulating the expression of the LDLR proteins undernormal and especially, neurodegenerative conditions.A first study was conducted to evaluate potential variations in PCSK9 expressionin the brain of autopsy-confirmed AD compared to age-matched control subjects. Agenetic association study was also performed to determine the effect of five commonPCSK9 polymorphisms on AD risk and modulation of gene expression. Using theentorhinal cortex lesion (ECL) model in a second study, a role for PCSK9 in reactivesynaptogenesis was evaluated in response to brain damage in this in vivo paradigm inmice. A third study investigated in an in vitro model of reactive neuronal plasticity, theeffect of PCSK9 on synaptogenesis and remodelling processes in response to neuronalinjury.The results show a cortical and hippocampal upregulation of PCSK9 expression inthe brain of end-stages AD patients which do not result from the five studied geneticvariants. No correlations were observed for PCSK9 with markers of AD pathology;suggesting an involvement of PCSK9 in response to neurodegeneration. Consistent withthis idea, PCSK9 levels were increased during the active phase of neuronal membraneremodelling following ECL. In vitro, overexpression of PCSK9 in normal or neuronallikecells undergoing post-injury reactive plasticity caused increased synaptic densitywhich supports a role for PCSK9 in synaptogenesis and plasticity. While PCSK9 wasfound to negatively affect the LDLR levels in AD brains and both the LDLR and apoER2during reactive plasticity in vitro, levels of the LDLR in ECL mice was not affected byPCSK9 but instead, together with apoE, levels were upregulated in the early phase ofsynaptic remodelling.Together, these findings indicate that PCSK9 plays an important role incompensatory neuronal repair associated with age, brain injury or chronic degeneration asfound in AD. Its expression in the brain possibly regulates cholesterol homeostasis and/orsignalling pathways mediated by the apoE/LDLR pathway or other members of theLDLR family during axonal and synaptic remodelling. These findings are consistent withthe relationship that exists between lipid homeostatic processes and AD pathology andindicate that PCSK9 may be a new player in the regulation of these processes that worthsfurther investigation in a context of neurodegenerative disorders.
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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 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".