Filipin Levels as Potential Predictors of Alzheimer’s Disease Risk
Affiliation(s)
Division of Human Anatomy, Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Division of Human Anatomy, Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA, USA.
ABSTRACT
To date, therapies to prevent or treat Alzheimer’s disease (AD) have largely focused on removing excess aggregation-prone amyloid peptide Aβ from the brain, an approach that has produced disappointing clinical outcomes. An alternative hypothesis proposes that Aβ production and aggregation is a symptom of a larger, systemic disease affecting the regulation of lipids, including cholesterol. In this scenario, lipid dysregulation would likely occur early in the disease process, making it an ideal target for predicting risk of mild cognitive impairment (MCI) to AD conversion. Here, we report that levels of filipin, a fluorescent polyene macrolide widely used as a diagnostic tool for diseases of lipid dysregulation, correlate with cellular damage caused by 27-hydroxycholesterol and with dementia status in human peripheral blood cells. These results provide strong preliminary data suggesting that filipin could be of use in the development of a quick and inexpensive method to measure the risk of AD conversion in patients with MCI, supplementing existing testing strategies that focus on the consequences of Aβ accumulation.
To date, therapies to prevent or treat Alzheimer’s disease (AD) have largely focused on removing excess aggregation-prone amyloid peptide Aβ from the brain, an approach that has produced disappointing clinical outcomes. An alternative hypothesis proposes that Aβ production and aggregation is a symptom of a larger, systemic disease affecting the regulation of lipids, including cholesterol. In this scenario, lipid dysregulation would likely occur early in the disease process, making it an ideal target for predicting risk of mild cognitive impairment (MCI) to AD conversion. Here, we report that levels of filipin, a fluorescent polyene macrolide widely used as a diagnostic tool for diseases of lipid dysregulation, correlate with cellular damage caused by 27-hydroxycholesterol and with dementia status in human peripheral blood cells. These results provide strong preliminary data suggesting that filipin could be of use in the development of a quick and inexpensive method to measure the risk of AD conversion in patients with MCI, supplementing existing testing strategies that focus on the consequences of Aβ accumulation.
KEYWORDS
Alzheimer’s Disease, Lipid Dysregulation, Cholesterol, Mild Cognitive Impairment, Filipin Levels
Alzheimer’s Disease, Lipid Dysregulation, Cholesterol, Mild Cognitive Impairment, Filipin Levels
Cite this paper
Castello, M. , Howard, K. , Castaneda, A. and Soriano, S. (2014) Filipin Levels as Potential Predictors of Alzheimer’s Disease Risk. Advances in Alzheimer's Disease, 3, 137-144. doi: 10.4236/aad.2014.33013.
Castello, M. , Howard, K. , Castaneda, A. and Soriano, S. (2014) Filipin Levels as Potential Predictors of Alzheimer’s Disease Risk. Advances in Alzheimer's Disease, 3, 137-144. doi: 10.4236/aad.2014.33013.
References
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http://dx.doi.org/10.1016/j.mcn.2009.07.013 [9] Naj, A.C., Jun, G., Beecham, G.W., Wang, L.-S., Vardarajan, B.N., Buros, J., et al. (2011) Common Variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 Are Associated with Late-Onset Alzheimer’s Disease. Nature Genetics, 43, 436-441. http://dx.doi.org/10.1038/ng.801 [10] Björkhem, I. (2012) Five Decades with Oxysterols. Biochimie, 95, 448-454.
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http://dx.doi.org/10.1111/j.1471-4159.2008.05736.x [15] Prasanthi, J.R.P., Huls, A., Thomasson, S., Thompson, A., Schommer, E. and Ghribi, O. (2009) Differential Effects of 24-hydroxycholesterol and 27-hydroxycholesterol on β-Amyloid Precursor Protein Levels and Processing in Human Neuroblastoma SH-SY5Y Cells. Molecular Neurodegeneration, 4, 1.
http://dx.doi.org/10.1186/1750-1326-4-1 [16] Burg, V.K., Grimm, H.S., Rothhaar, T.L., Grösgen, S., Hundsdörfer, B., Haupenthal, V.J., et al. (2013) Plant Sterols the Better Cholesterol in Alzheimer’s Disease? A Mechanistical Study. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 33, 16072-16087.
http://dx.doi.org/10.1523/JNEUROSCI.1506-13.2013 [17] Argoff, C.E., Kaneski, C.R., Blanchette-Mackie, E.J., Comly, M., Dwyer, N.K., Brown, A., Brady, R.O. and Pentchev, P.G. (1990) Type C Niemann-Pick Disease: Documentation of Abnormal LDL Processing in Lymphocytes. Biochemical and Biophysical Research Communications, 171, 38-45.
http://dx.doi.org/10.1016/0006-291X(90)91353-T [18] Distl, R., Treiber-Held, S., Albert, F., Meske, V., Harzer, K. and Ohm, T.G. (2003) Cholesterol Storage and Tau Pathology in Niemann-Pick Type C Disease in the Brain. The Journal of Pathology, 200, 104-111. http://dx.doi.org/10.1002/path.1320 [19] Tamul, K.R., Schmitz, J.L., Kane, K. and Folds, J.D. (1995) Comparison of the Effects of Ficoll-Hypaque Separation and Whole Blood Lysis on Results of Immunophenotypic Analysis of Blood and Bone Marrow Samples from Patients with Hematologic Malignancies. Clinical and Diagnostic Laboratory Immunology, 2, 337-342. [20] Koh, C.H.V. and Cheung, N.S. (2006) Cellular Mechanism of U18666A-Mediated Apoptosis in Cultured Murine Cortical Neurons: Bridging Niemann-Pick Disease Type C and Alzheimer’s Disease. Cellular Signalling, 18, 1844-1853. http://dx.doi.org/10.1016/j.cellsig.2006.04.006 [21] Cenedella, R.J. (2009) Cholesterol Synthesis Inhibitor U18666A and the Role of Sterol Metabolism and Trafficking in Numerous Pathophysiological Processes. Lipids, 44, 477-487.
http://dx.doi.org/10.1007/s11745-009-3305-7 [22] Arthur, J.R., Heinecke, K.A. and Seyfried, T.N. (2011) Filipin Recognizes both GM1 and Cholesterol in GM1 Gangliosidosis Mouse brain. Journal of Lipid Research, 52, 1345-1351.
http://dx.doi.org/10.1194/jlr.M012633 [23] Mandas, A., Abete, C., Putzu, P.F., la Colla, P., Dessì, S. and Pani, A. (2012) Changes in Cholesterol Metabolism- Related Gene Expression in Peripheral Blood Mononuclear Cells from Alzheimer Patients. Lipids in Health and Disease, 11, 39. http://dx.doi.org/10.1186/1476-511X-11-39
[1] Alzheimer’s Association (2013) 2013 Alzheimer’s Disease Facts and Figures. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 9, 208-245. http://dx.doi.org/10.1016/j.jalz.2013.02.003 [2] Golde, T.E., Petrucelli, L. and Lewis, J. (2010) Targeting Aβ and Tau in Alzheimer’s Disease, an Early Interim Report. Experimental Neurology, 223, 252-266. http://dx.doi.org/10.1016/j.expneurol.2009.07.035 [3] Castellani, R.J. and Perry, G. (2012) Pathogenesis and Disease-Modifying Therapy in Alzheimer’s Disease: The Flat Line of Progress. Archives of Medical Research, 43, 694-698.
http://dx.doi.org/10.1016/j.arcmed.2012.09.009 [4] Castello, M.A. and Soriano, S. (2014) On the Origin of Alzheimer’s Disease. Trials and Tribulations of the Amyloid Hypothesis. Ageing Research Reviews, 13C, 10-12. http://dx.doi.org/10.1016/j.arr.2013.10.001 [5] Castello, M.A. and Soriano, S. (2013) Rational Heterodoxy: Cholesterol Reformation of the Amyloid Doctrine. Ageing Research Reviews, 12, 282-288. http://dx.doi.org/10.1016/j.arr.2012.06.007 [6] Rodríguez-Rodríguez, E., Mateo, I., Infante, J., Llorca, J., García-Gorostiaga, I., Vázquez-Higuera, J.L. et al. (2009) Interaction between HMGCR and ABCA1 Cholesterol-Related Genes Modulates Alzheimer’s Disease Risk. Brain Research, 1280, 166-171. http://dx.doi.org/10.1016/j.brainres.2009.05.019 [7] Jones, L., Holmans, P.A., Hamshere, M.L., Harold, D., Moskvina, V., Ivanov, D., et al. (2010) Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer’s Disease. PLoS ONE, 5, Article ID: e13950. http://dx.doi.org/10.1371/journal.pone.0013950 [8] Liu, J.-P., Tang, Y., Zhou, S., Toh, B.H., McLean, C. and Li, H. (2010) Cholesterol Involvement in the Pathogenesis of Neurodegenerative Diseases. Molecular and Cellular Neuroscience, 43, 33-42.
http://dx.doi.org/10.1016/j.mcn.2009.07.013 [9] Naj, A.C., Jun, G., Beecham, G.W., Wang, L.-S., Vardarajan, B.N., Buros, J., et al. (2011) Common Variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 Are Associated with Late-Onset Alzheimer’s Disease. Nature Genetics, 43, 436-441. http://dx.doi.org/10.1038/ng.801 [10] Björkhem, I. (2012) Five Decades with Oxysterols. Biochimie, 95, 448-454.
http://dx.doi.org/10.1016/j.biochi.2012.02.029 [11] Pani, A., Dessì, S., Diaz, G., La Colla, P., Abete, C., Mulas, C., et al. (2009) Altered Cholesterol Ester Cycle in Skin Fibroblasts from Patients with Alzheimer’s Disease. Journal of Alzheimer’s Disease: JAD, 18, 829-841. [12] Pani, A., Mandas, A., Diaz, G., Abete, C., Cocco, P.L., Angius, F., et al. (2009) Accumulation of Neutral Lipids in Peripheral Blood Mononuclear Cells as a Distinctive Trait of Alzheimer Patients and Asymptomatic Subjects at Risk of Disease. BMC Medicine, 7, 66. http://dx.doi.org/10.1186/1741-7015-7-66 [13] Ghribi, O., Larsen, B., Schrag, M. and Herman, M.M. (2006) High Cholesterol Content in Neurons Increases BACE, β-Amyloid, and Phosphorylated Tau Levels in Rabbit Hippocampus. Experimental Neurology, 200, 460-467. http://dx.doi.org/10.1016/j.expneurol.2006.03.019 [14] Prasanthi, J.R.P., Feist, G., Thomasson, S., Thompson, A., Schommer, E. and Ghribi, O. (2008) Differential Effects of 24-Hydroxycholesterol and 27-Hydroxycholesterol on Tyrosine Hydroxylase and α-Synuclein in Human Neuroblastoma SH-SY5Y Cells. Journal of Neurochemistry, 107, 1722-1729.
http://dx.doi.org/10.1111/j.1471-4159.2008.05736.x [15] Prasanthi, J.R.P., Huls, A., Thomasson, S., Thompson, A., Schommer, E. and Ghribi, O. (2009) Differential Effects of 24-hydroxycholesterol and 27-hydroxycholesterol on β-Amyloid Precursor Protein Levels and Processing in Human Neuroblastoma SH-SY5Y Cells. Molecular Neurodegeneration, 4, 1.
http://dx.doi.org/10.1186/1750-1326-4-1 [16] Burg, V.K., Grimm, H.S., Rothhaar, T.L., Grösgen, S., Hundsdörfer, B., Haupenthal, V.J., et al. (2013) Plant Sterols the Better Cholesterol in Alzheimer’s Disease? A Mechanistical Study. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 33, 16072-16087.
http://dx.doi.org/10.1523/JNEUROSCI.1506-13.2013 [17] Argoff, C.E., Kaneski, C.R., Blanchette-Mackie, E.J., Comly, M., Dwyer, N.K., Brown, A., Brady, R.O. and Pentchev, P.G. (1990) Type C Niemann-Pick Disease: Documentation of Abnormal LDL Processing in Lymphocytes. Biochemical and Biophysical Research Communications, 171, 38-45.
http://dx.doi.org/10.1016/0006-291X(90)91353-T [18] Distl, R., Treiber-Held, S., Albert, F., Meske, V., Harzer, K. and Ohm, T.G. (2003) Cholesterol Storage and Tau Pathology in Niemann-Pick Type C Disease in the Brain. The Journal of Pathology, 200, 104-111. http://dx.doi.org/10.1002/path.1320 [19] Tamul, K.R., Schmitz, J.L., Kane, K. and Folds, J.D. (1995) Comparison of the Effects of Ficoll-Hypaque Separation and Whole Blood Lysis on Results of Immunophenotypic Analysis of Blood and Bone Marrow Samples from Patients with Hematologic Malignancies. Clinical and Diagnostic Laboratory Immunology, 2, 337-342. [20] Koh, C.H.V. and Cheung, N.S. (2006) Cellular Mechanism of U18666A-Mediated Apoptosis in Cultured Murine Cortical Neurons: Bridging Niemann-Pick Disease Type C and Alzheimer’s Disease. Cellular Signalling, 18, 1844-1853. http://dx.doi.org/10.1016/j.cellsig.2006.04.006 [21] Cenedella, R.J. (2009) Cholesterol Synthesis Inhibitor U18666A and the Role of Sterol Metabolism and Trafficking in Numerous Pathophysiological Processes. Lipids, 44, 477-487.
http://dx.doi.org/10.1007/s11745-009-3305-7 [22] Arthur, J.R., Heinecke, K.A. and Seyfried, T.N. (2011) Filipin Recognizes both GM1 and Cholesterol in GM1 Gangliosidosis Mouse brain. Journal of Lipid Research, 52, 1345-1351.
http://dx.doi.org/10.1194/jlr.M012633 [23] Mandas, A., Abete, C., Putzu, P.F., la Colla, P., Dessì, S. and Pani, A. (2012) Changes in Cholesterol Metabolism- Related Gene Expression in Peripheral Blood Mononuclear Cells from Alzheimer Patients. Lipids in Health and Disease, 11, 39. http://dx.doi.org/10.1186/1476-511X-11-39