The dual behavior of PCSK9 in the regulation of apoptosis is crucial in Alzheimer's disease progression (Review)

Wu,Qi; Tang,Zhi‑Han; Peng,Juan; Liao,Ling; Pan,Li‑Hong; Wu,Chun‑Yan; Jiang,Zhi‑Sheng; Wang,Gui‑Xue; Liu,Lu‑Shan

doi:10.3892/br.2013.213

The dual behavior of PCSK9 in the regulation of apoptosis is crucial in Alzheimer's disease progression (Review)

Authors:
- Qi Wu
- Zhi‑Han Tang
- Juan Peng
- Ling Liao
- Li‑Hong Pan
- Chun‑Yan Wu
- Zhi‑Sheng Jiang
- Gui‑Xue Wang
- Lu‑Shan Liu
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Affiliations: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China
Published online on: December 30, 2013 https://doi.org/10.3892/br.2013.213
Pages: 167-171

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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 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.

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1	Maxwell KN, Soccio RE, Duncan EM, Sehayek E and Breslow JL: Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res. 44:2109–2119. 2003. View Article : Google Scholar : PubMed/NCBI
2	Seidah NG, Benjannet S, Wickham L, et al: The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA. 100:928–933. 2003. View Article : Google Scholar
3	Seidah NG: PCSK9 as a therapeutic target of dyslipidemia. Expert Opin Ther Targets. 13:19–28. 2009. View Article : Google Scholar : PubMed/NCBI
4	Cohen JC, Boerwinkle E, Mosley TH Jr and Hobbs HH: Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 354:1264–1272. 2006. View Article : Google Scholar : PubMed/NCBI
5	Stein EA, Gipe D, Bergeron J, et al: Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 380:29–36. 2012.
6	Hall SS: Genetics: a gene of rare effect. Nature. 496:152–155. 2013. View Article : Google Scholar : PubMed/NCBI
7	Brown MS and Goldstein JL: Biomedicine. Lowering LDL - not only how low, but how long? Science. 311:1721–1723. 2006. View Article : Google Scholar : PubMed/NCBI
8	Wu CY, Tang ZH, Jiang L, Li XF, Jiang ZS and Liu LS: PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3 pathway. Mol Cell Biochem. 359:347–358. 2012. View Article : Google Scholar : PubMed/NCBI
9	Tang Z, Jiang L, Peng J, et al: PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-κB activation in THP-1-derived macrophages. Int J Mol Med. 30:931–938. 2012.PubMed/NCBI
10	Sun X, Essalmani R, Day R, Khatib AM, Seidah NG and Prat A: Proprotein convertase subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver. Neoplasia. 14:1122–1131. 2012.PubMed/NCBI
11	Poirier S, Prat A, Marcinkiewicz E, et al: Implication of the proprotein convertase NARC-1/PCSK9 in the development of the nervous system. J Neurochem. 98:838–850. 2006. View Article : Google Scholar : PubMed/NCBI
12	Citron M: Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov. 9:387–398. 2010.
13	Cunningham C, Wilcockson DC, Campion S, Lunnon K and Perry VH: Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci. 25:9275–9284. 2005. View Article : Google Scholar
14	Verhamme P, Quarck R, Hao H, et al: Dietary cholesterol withdrawal reduces vascular inflammation and induces coronary plaque stabilization in miniature pigs. Cardiovasc Res. 56:135–144. 2002. View Article : Google Scholar : PubMed/NCBI
15	Nematbakhsh M, Haghjooyjavanmard S, Mahmoodi F and Monajemi AR: The prevention of endothelial dysfunction through endothelial cell apoptosis inhibition in a hypercholesterolemic rabbit model: the effect of L-arginine supplementation. Lipids Health Dis. 7:272008. View Article : Google Scholar
16	Kankaanpaa J, Turunen SP, Moilanen V, Horkko S and Remes AM: Cerebrospinal fluid antibodies to oxidized LDL are increased in Alzheimer’s disease. Neurobiol Dis. 33:467–472. 2009.PubMed/NCBI
17	Martins IJ, Berger T, Sharman MJ, Verdile G, Fuller SJ and Martins RN: Cholesterol metabolism and transport in the pathogenesis of Alzheimer’s disease. J Neurochem. 111:1275–1308. 2009.
18	Chiang LW, Grenier JM, Ettwiller L, et al: An orchestrated gene expression component of neuronal programmed cell death revealed by cDNA array analysis. Proc Natl Acad Sci USA. 98:2814–2819. 2001. View Article : Google Scholar : PubMed/NCBI
19	Bingham B, Shen R, Kotnis S, et al: Proapoptotic effects of NARC 1 (= PCSK9), the gene encoding a novel serine proteinase. Cytometry A. 69:1123–1131. 2006.PubMed/NCBI
20	Cameron J, Ranheim T, Kulseth MA, Leren TP and Berge KE: Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis. 201:266–273. 2008. View Article : Google Scholar : PubMed/NCBI
21	Ji HF and Shen L: Berberine: a potential multipotent natural product to combat Alzheimer’s disease. Molecules. 16:6732–6740. 2011.PubMed/NCBI
22	Kysenius K, Muggalla P, Matlik K, Arumae U and Huttunen HJ: PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Cell Mol Life Sci. 69:1903–1916. 2012. View Article : Google Scholar : PubMed/NCBI
23	Ranheim T, Mattingsdal M, Lindvall JM, et al: Genome-wide expression analysis of cells expressing gain of function mutant D374Y-PCSK9. J Cell Physiol. 217:459–467. 2008. View Article : Google Scholar : PubMed/NCBI
24	Di Paolo G and Kim TW: Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci. 12:284–296. 2011.
25	Jonas MC, Costantini C and Puglielli L: PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep. 9:916–922. 2008. View Article : Google Scholar : PubMed/NCBI
26	Ko MH and Puglielli L: Two endoplasmic reticulum (ER)/ER Golgi intermediate compartment-based lysine acetyltransferases post-translationally regulate BACE1 levels. J Biol Chem. 284:2482–2492. 2009. View Article : Google Scholar : PubMed/NCBI
27	Liu M, Wu G, Baysarowich J, et al: PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain. J Lipid Res. 51:2611–2618. 2010. View Article : Google Scholar : PubMed/NCBI
28	Shibata N, Ohnuma T, Higashi S, et al: No genetic association between PCSK9 polymorphisms and Alzheimer’s disease and plasma cholesterol level in Japanese patients. Psychiatr Genet. 15:2392005.
29	Reynolds CA, Hong MG, Eriksson UK, et al: Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk. Hum Mol Genet. 19:2068–2078. 2010. View Article : Google Scholar : PubMed/NCBI
30	Mattson MP and Camandola S: NF-κB in neuronal plasticity and neurodegenerative disorders. J Clin Invest. 107:247–254. 2001.
31	Sola S, Aranha MM and Rodrigues CM: Driving apoptosis-relevant proteins toward neural differentiation. Mol Neurobiol. 46:316–331. 2012. View Article : Google Scholar : PubMed/NCBI
32	Culmsee C and Plesnila N: Targeting Bid to prevent programmed cell death in neurons. Biochem Soc Trans. 34:1334–1340. 2006. View Article : Google Scholar : PubMed/NCBI
33	Wong HK, Fricker M, Wyttenbach A, et al: Mutually exclusive subsets of BH3-only proteins are activated by the p53 and c-Jun N-terminal kinase/c-Jun signaling pathways during cortical neuron apoptosis induced by arsenite. Mol Cell Biol. 25:8732–8747. 2005. View Article : Google Scholar : PubMed/NCBI
34	Lindsten T, Zong WX and Thompson CB: Defining the role of the Bcl-2 family of proteins in the nervous system. Neuroscientist. 11:10–15. 2005. View Article : Google Scholar : PubMed/NCBI
35	Almeida A: Genetic determinants of neuronal vulnerability to apoptosis. Cell Mol Life Sci. 70:71–88. 2013. View Article : Google Scholar : PubMed/NCBI
36	Gotz R, Karch C, Digby MR, Troppmair J, Rapp UR and Sendtner M: The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells. Hum Mol Genet. 9:2479–2489. 2000. View Article : Google Scholar : PubMed/NCBI
37	Baratchi S, Kanwar RK and Kanwar JR: Survivin: a target from brain cancer to neurodegenerative disease. Crit Rev Biochem Mol Biol. 45:535–554. 2010. View Article : Google Scholar : PubMed/NCBI
38	Dhandapani KM and Brann DW: Transforming growth factor-β: a neuroprotective factor in cerebral ischemia. Cell Biochem Biophys. 39:13–22. 2003.
39	Singh MH, Brooke SM, Zemlyak I and Sapolsky RM: Evidence for caspase effects on release of cytochrome c and AIF in a model of ischemia in cortical neurons. Neurosci Lett. 469:179–183. 2010. View Article : Google Scholar : PubMed/NCBI
40	Chiou SH, Chen SJ, Peng CH, et al: Fluoxetine up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-induced apoptosis in hippocampus-derived neural stem cell. Biochem Biophys Res Commun. 343:391–400. 2006. View Article : Google Scholar : PubMed/NCBI
41	Broughton BR, Reutens DC and Sobey CG: Apoptotic mechanisms after cerebral ischemia. Stroke. 40:e331–e339. 2009. View Article : Google Scholar : PubMed/NCBI
42	Blaise S, Kneib M, Rousseau A, et al: In vivo evidence that TRAF4 is required for central nervous system myelin homeostasis. PLoS One. 7:e309172012. View Article : Google Scholar : PubMed/NCBI
43	LeBlanc AC: The role of apoptotic pathways in Alzheimer’s disease neurodegeneration and cell death. Curr Alzheimer Res. 2:389–402. 2005.
44	Joseph D’Ercole A and Ye P: Expanding the mind: insulin-like growth factor I and brain development. Endocrinology. 149:5958–5962. 2008.PubMed/NCBI
45	McCarthy MJ, Rubin LL and Philpott KL: Involvement of caspases in sympathetic neuron apoptosis. J Cell Sci. 110(Pt 18): 2165–2173. 1997.PubMed/NCBI
46	Ludwig-Galezowska AH, Flanagan L and Rehm M: Apoptosis repressor with caspase recruitment domain, a multifunctional modulator of cell death. J Cell Mol Med. 15:1044–1053. 2011. View Article : Google Scholar : PubMed/NCBI
47	Gora-Kupilas K and Josko J: The neuroprotective function of vascular endothelial growth factor (VEGF). Folia Neuropathol. 43:31–39. 2005.PubMed/NCBI
48	Krantic S, Mechawar N, Reix S and Quirion R: Apoptosis-inducing factor: a matter of neuron life and death. Prog Neurobiol. 81:179–196. 2007. View Article : Google Scholar : PubMed/NCBI