Neuronal apoptosis is crucial in neurodegenerative diseases. However, a lower apoptotic rate of nerve cells is detected in the brain compared to that in other organs in neurodegenerative patients or in animal models, suggesting that neuronal apoptosis induced by any type of risk factors is intricately regulated. Human and animal studies demonstrated that a high concentration of oxidized LDL (ox‑LDL) in the brain, which is associated with hyperlipidemia, is one of the key apoptosis inducers in neurodegenerative diseases. However, the mechanism underlying the ox‑LDL‑mediated regulation of neuronal apoptosis has not been fully elucidated. Recently, we investigated proprotein convertase subtilisin̸kexin type 9 (PCSK9), a striking gene involved in lipid metabolism that exhibits a positive correlation with macrophage and endothelial cell apoptosis induced by ox‑LDL. Moreover, PCSK9 may degrade β‑site amyloid precursor protein‑cleaving enzyme 1 (BACE1), the key enzyme cleaving amyloid precursor protein (APP) to generate amyloid β peptide (Aβ). Aβ is another key apoptosis inducer in neurodegenerative diseases. Our findings indicated that PCSK9 may be upregulated by the high levels of ox‑LDL in the brain associated with hyperlipidemia and promote neuronal apoptosis through the NF‑κB‑B‑cell lymphoma 2 (Bcl‑2)/Bax‑caspase 9‑caspase 3 signaling pathways. Moreover, increased PCSK9 levels may inhibit the APP̸Aβ metabolic pathway and reduce Aβ generation by degrading BACE1, thereby decreasing Aβ‑induced neuronal apoptosis. The dual regulation mechanism of PCSK9 on apoptosis maintains neuronal apoptosis induced by risk factors at low levels.

Hyperlipidemia is a risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a lipid regulatory gene involved in cell apoptosis. However, the function and mechanism of PCSK9 in neuronal apoptosis following hyperlipidemia remains to be elucidated. The present study established a hyperlipidemic mouse model by feeding a high‑fat diet (HFD) to 6‑week‑old apoE(‑/‑) mice. Plasma lipid levels, hippocampal lipid accumulation, hippocampal histology, and hippocampal neuronal apoptosis were all monitored for changes. The expression levels of PCSK9, β‑secretase 1 (BACE1), B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), and caspase‑3 in hippocampal CA3 and CA1 neurons were also measured. Results demonstrated that a HFD increased the lipid accumulation in the CA3 hippocampus and the levels of plasma lipids, including triglycerides, total cholesterol, low‑density lipoprotein, and high‑density lipoprotein. In addition, CA3 neurons in the HFD group indicated apparent injuries and increased neuronal apoptosis, which are associated with the expression of Bcl‑2, Bax, and caspase‑3. A HFD also increased the expression levels of PCSK9 and BACE1. BACE1 promotes cleavage of amyloid precursor proteins to generate β‑amyloid peptide (Aβ), which induces neuronal apoptosis. Protein levels of Aβ are associated with the observation of amyloid plaques in the hippocampus of the HFD group. The results suggest that hyperlipidemia regulates neuronal apoptosis by increasing PCSK9 and BACE1 expression. Overall, the current study may elucidate the role of lipid metabolism disorder in AD pathogenesis.

Heart failure (HF) is a complex clinical syndrome caused by various cardiovascular diseases. Its main pathogenesis includes cardiomyocyte loss, myocardial energy metabolism disorder, and activation of cardiac inflammation. Due to the clinically unsatisfactory treatment of heart failure, different mechanisms need to be explored to provide new targets for the treatment of this disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a gene mainly related to familial hypercholesterolemia, was discovered in 2003. Aside from regulating lipid metabolism, PCSK9 may be involved in other biological processes such as apoptosis, autophagy, pyroptosis, inflammation, and tumor immunity and related to diabetes and neurodegenerative diseases. Recently, clinical data have shown that the circulating PCSK9 level is significantly increased in patients with heart failure, and it is related to the prognosis for heart failure. Furthermore, in animal models and patients with myocardial infarction, PCSK9 in the infarct margin area was also found to be significantly increased, which further suggested that PCSK9 might be closely related to heart failure. However, the specific mechanism of how PCSK9 participates in heart failure remains to be further explored. The purpose of this review is to summarize the potential mechanism of PCSK9's involvement in heart failure, thereby providing a new treatment strategy for heart failure.