title: The dual behavior of PCSK9 in the regulation of apoptosis is crucial in Alzheimer's disease progression (Review).
abstract: 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 subtilisin/kexin 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 APP/Aβ 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.
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China ; Bioengineering College of Chongqing University, Chongqing 400044, P.R. China.
authors.forename: Zhi-Han
authors.initials: ZH
authors.lastname: Tang
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Peng
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Liao
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Pan
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Zhi-Sheng
authors.initials: ZS
authors.lastname: Jiang
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China ; Bioengineering College of Chongqing University, Chongqing 400044, P.R. China.
authors.forename: Gui-Xue
authors.initials: GX
authors.lastname: Wang
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Lu-Shan
authors.initials: LS
authors.lastname: Liu
keywords: Alzheimer’s disease; amyloid β peptide; apoptosis; oxidized low-density lipoprotein; proprotein convertase subtilisin/kexin type 9; β-site amyloid precursor protein-cleaving enzyme 1