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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. [ABSTRACT FROM AUTHOR]