Changes in cholesterol metabolism-related gene expression in peripheral blood mononuclear cells from Alzheimer patients

Lipids in Health and Disease

Alessandra Pani²  Sandra Dessì¹  Paolo la Colla²  Paolo Francesco Putzu¹  Claudia Abete¹  Antonella Mandas¹ 

[1] Department of Internal Medicine, University of Cagliari, Cittadella Universitaria, 09042- Monserrato (CA) Italy;Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, 09042- Monserrato (CA) Italy

关键词: Biomarker;    Neutral lipids;    Amyloid precursor protein;    Cholesterol esters;    Cholesterol;    Blood cells;    Alzheimer disease;   

Others  :  1160332
DOI  :  10.1186/1476-511X-11-39

 received in 2012-01-31, accepted in 2012-03-14,  发布年份 2012

【 摘 要 】

Background

Cholesterol homeostasis dysfunction has been reported to have role in the pathogenesis of Alzheimer disease (AD). Therefore, changes in cholesterol metabolism in blood components may help to develop new potential AD biomarkers. In this study changes in cholesterol metabolism-related gene expression genes were evaluated in peripheral blood mononuclear cells (PBMCs) from AD subjects, their first degree relatives (FDR) and two groups of age matched controls (C1 > 80 years, C2 < 60 years). The expression of three genes related to APP processing was also determined.

Results

Results showed significantly different behavior (P = 0.000) in the expression of all analyzed genes among the 4 groups. An inverse correlation emerged between the age of controls and the propensity of their PBMCs to express selected genes. Moreover, when gene expression was evaluated in PBMCs from AD patients and compared with that of PBMCs from healthy subjects of the same age, LDL-R and APP mRNAs were most abundant in AD as compared C1 whereas SREBP-2 and particularly nCEH were present at much lower mRNA levels in AD-PBMCs. This study describes for the first time a differential expression profile of cholesterol and APP related genes in PBMCs from AD patients and their FDR.

Conclusions

We suggest that the expressions of cholesterol homeostasis and APP processing related genes in PBMC could be proposed as possible biomarkers to evaluate AD risk. In addition, gene expression in PBMC could be also used for diagnosis and development of therapeutic strategies as well as for personalized prediction in clinical outcome of AD.

【 授权许可】

   
2012 Mandas et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Reddy PH, Beal MF: Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med 2008, 14:45-53.
• [2]Small DH: Network dysfunction in Alzheimer's disease: does synaptic scaling drive disease progression? Trends Mol Med 2008, 14:103-108.
• [3]Zhang YW, Xu H: Molecular and cellular mechanisms for Alzheimer's disease: understanding APP metabolism. Curr Mol Med 2007, 7:687-696.
• [4]Puglielli L, Tanzi RE, Kovacs DM: Alzheimer's disease: the cholesterol connection. Nat Neurosci 2003, 6:345-351.
• [5]Ghribi O, Larsen B, Schrag M, Herman MM: High cholesterol content in neurons increases BACE, β-amyloid, and phosphorylated tau levels in rabbit hippocampus. Exper Neurol 2006, 200:460-467.
• [6]Huttunen HJ, Puglielli L, Ellis BC, MacKenzie Ingano LA, Kovacs DM: Novel N-terminal cleavage of APP precludes Abeta generation in ACAT-defective AC29 cells. J Mol Neurosci 2009, 37:6-15.
• [7]Puglielli L, Konopka G, Pack-Chung E, Ingano LA, Berezovska O, Hyman BT, et al.: Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol 2001, 3:905-912.
• [8]Hutter-Paier B, Huttunen HJ, Puglielli L, Eckman CB, Kim DY, Hofmeister A, et al.: The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron 2004, 44:227-238.
• [9]Puglielli L, Ellis BC, Ingano LA, Kovacs DM: Role of acyl-coenzyme a: cholesterol acyltransferase activity in the processing of the amyloid precursor protein. J Mol Neurosci 2004, 24:93-96.
• [10]Huttunen HJ, Kovacs DM: ACAT as a drug target for Alzheimer's disease. Neurodegener Dis 2008, 5:212-214.
• [11]Bryleva EY, Rogers MA, Chang CC, Buen F, Harris BT, Rousselet E, et al.: ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proc Natl Acad Sci USA 2010, 107:3081-3086.
• [12]Dietschy JM, Turley SD: Cholesterol metabolism in the brain. Curr Opin Lipidol 2001, 12:105-112.
• [13]Pani A, Dessì S, Diaz G, La Colla P, Abete C, Mulas C, et al.: Altered cholesterol ester cycle in skin fibroblasts from patients with Alzheimer's disease. J Alzheimers Dis 2009, 18:829-841.
• [14]Pani A, Mandas A, Diaz G, Abete C, Cocco PL, Angius F, et al.: Accumulation of neutral lipids in peripheral blood mononuclear cells as a distinctive trait of Alzheimer patients and asymptomatic subjects at risk of disease. BMC Med 2009, 7:66. BioMed Central Full Text
• [15]Pani A, Mandas A, Dessì S: Cholesterol, Alzheimer's disease, prion disorders: a ménage à trois? Curr Drug Targets 2010, 11:1018-1031.
• [16]McShea A, Lee HG, Petersen RB, Casadesus G, Vincent I, Linford NJ, et al.: Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. Biochim Biophys Acta 2007, 1772:467-472.
• [17]Moreira PI, Santos MS, Oliveira CR, Shenk JC, Nunomura A, Smith MA, et al.: Alzheimer disease and the role of free radicals in the pathogenesis of the disease. CNS Neurol Disord Drug Targets 2008, 7:3-10.
• [18]Wang X, Su B, Zheng L, Perry G, Smith MA, Zhu X: The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease. J Neurochem 2009, 109:153-159.
• [19]Kepe V, Huang SC, Small GW, Satyamurthy N, Barrio JR: Visualizing pathology deposits in the living brain of patients with Alzheimer's disease. Methods Enzymol 2006, 412:144-160.
• [20]Beela AJ, Sakakuraa M, Barretta PJ, Sanders CR: Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid-Alzheimer's disease relationships? BBA - Mol Cell Biol Lipid 2010, 1801:975-982.
• [21]Kim J, Basak JM, Holtzman DM: The Role of Apolipoprotein E in Alzheimer's Disease. Neuron 2009, 63:287-303.
• [22]Gustaw-Rothenberg K, Lerner A, Bonda DJ, Lee HG, Zhu X, Perry G, et al.: Biomarkers in Alzheimer's disease: past, present and future. Biomark Med 2010, 4:15-26.
• [23]Gasparini L, Racchi M, Binetti G, Trabucchi M, Solerte SB, Alkon D, et al.: Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease. FASEB J 1998, 12:17-34.
• [24]Dietschy JM, Turley SD: Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 2004, 45:1375-1397.
• [25]Paz Marzolo M, Bu G: Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer's disease. Semin Cell Dev Biol 2009, 20:191-200.
• [26]Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, et al.: Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000, 283:1571-1577.
• [27]Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al.: Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003, 39:409-421.
• [28]Xiong L, Gaspar C, Rouleau GA: Genetics of Alzheimer's Disease and Research Frontiers in Dementia. Ger Aging 2005, 8:31-35.