Blood Bioenergetic Biomarkers in Alzheimer’s Disease APOE ε4-Carriers

Background:This study examined the impact of APOE ε4 on blood cell bioenergetics. Prior studies have shown systemic alterations in blood cells from APOE ε4 carriers.Methods:Platelet mitochondria cytochrome oxidase (COX) and citrate synthase (CS) Vmax activities were measured in APOE ε4 carrier and non-carrier Alzheimer’s disease (AD) subjects, and lymphocyte mitochondria and bioenergetics-relevant protein and viability endpoints were measured using fresh and expanded cultures. Statistical analysis was completed using Student’s T-Test.Results:The mean platelet COX Vmax activity, normalized to protein content, was lower in APOE ε4 carriers and lymphocyte Annexin V, a marker of apoptosis, was significantly higher. PINK1, a protein involved in mitophagy, was higher in APOE ε4 carrier lymphocytes. mTOR and SIRT1, which play a role in energy sensing, were different between the groups; mTOR phosphorylation decreased while SIRT1 phosphorylation increased in APOE ε4 carrier lymphocytes. The lipid synthesis pathway differed, as AceCSI and ATP CL increased in APOE ε4 carrier lymphocytes, and ACC phosphorylation also increased.Conclusions:These findings overall support a relationship between APOE genotype and bioenergetic pathways and indicate that relative to AD non-APOE ε4 carriers, platelets and lymphocytes from AD APOE ε4 carriers exist in a relative state of bioenergetic stress. As APOE ε4 influences AD risk these data may help define a systemic AD biomarker phenotype.

[1]  Meic H. Schmidt,et al.  Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship. , 2019, Advances in biological regulation.

[2]  J. Pell,et al.  Association between APOE e4 and white matter hyperintensity volume, but not total brain volume or white matter integrity , 2019, Brain Imaging and Behavior.

[3]  R. Swerdlow,et al.  Rasagiline for amyotrophic lateral sclerosis: A randomized, controlled trial , 2018, Muscle & nerve.

[4]  A. Annoni,et al.  Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation , 2018, Nature Communications.

[5]  Steven E. Arnold,et al.  Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums , 2018, Nature Reviews Neurology.

[6]  J. Molinuevo,et al.  Higher prevalence of cerebral white matter hyperintensities in homozygous APOE-ɛ4 allele carriers aged 45–75: Results from the ALFA study , 2017, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  M. D. de Leon,et al.  Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery , 2017, PloS one.

[8]  F. Barkhof,et al.  Disrupted white matter structural networks in healthy older adult APOE ε4 carriers – An international multicenter DTI study , 2017, Neuroscience.

[9]  R. Swerdlow,et al.  Platelet cytochrome oxidase and citrate synthase activities in APOE ε4 carrier and non-carrier Alzheimer's disease patients , 2017, Redox biology.

[10]  R. Swerdlow,et al.  A Mitochondrial Biomarker-Based Study of S-Equol in Alzheimer's Disease Subjects: Results of a Single-Arm, Pilot Trial. , 2017, Journal of Alzheimer's disease : JAD.

[11]  M. Lazarou,et al.  Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. , 2016, Trends in cell biology.

[12]  E. Tsilibary,et al.  The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific , 2016, Scientific Reports.

[13]  A. Fonteh,et al.  White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease , 2015, EBioMedicine.

[14]  A. Meyer-Lindenberg,et al.  Apolipoprotein E-dependent load of white matter hyperintensities in Alzheimer’s disease: a voxel-based lesion mapping study , 2015, Alzheimer's Research & Therapy.

[15]  R. Swerdlow,et al.  A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement , 2015, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.

[16]  A. Tee,et al.  mTOR and autophagy: a dynamic relationship governed by nutrients and energy. , 2014, Seminars in cell & developmental biology.

[17]  A. Vaquero,et al.  Sirtuins in stress response: guardians of the genome , 2014, Oncogene.

[18]  J. Rusted,et al.  Cognitive and neural signatures of the APOE E4 allele in mid-aged adults , 2014, Neurobiology of Aging.

[19]  Joanna M. Wardlaw,et al.  Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936☆ , 2014, Neurobiology of Aging.

[20]  Degui Zhi,et al.  The Bioenergetic Health Index: a new concept in mitochondrial translational research , 2014, Clinical science.

[21]  Xue Hua,et al.  Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. , 2014, JAMA neurology.

[22]  R. Swerdlow,et al.  Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines. , 2013, Human molecular genetics.

[23]  J. Viña,et al.  Lymphocytes from young healthy persons carrying the ApoE4 allele overexpress stress-related proteins involved in the pathophysiology of Alzheimer's disease. , 2012, Journal of Alzheimer's disease : JAD.

[24]  Xiaoling Li.  SIRT1 and energy metabolism. , 2013, Acta biochimica et biophysica Sinica.

[25]  R. Mahley,et al.  Apolipoprotein E Sets the Stage: Response to Injury Triggers Neuropathology , 2012, Neuron.

[26]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[27]  Paul M. Matthews,et al.  Differential effects of the APOE genotype on brain function across the lifespan , 2011, NeuroImage.

[28]  M. D. de Leon,et al.  Reduced mitochondria cytochrome oxidase activity in adult children of mothers with Alzheimer's disease. , 2011, Journal of Alzheimer's disease : JAD.

[29]  R. Mahley,et al.  Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease* , 2010, The Journal of Biological Chemistry.

[30]  A. Roses.  An inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease. , 2010, Archives of neurology.

[31]  E. Reiman,et al.  Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer's susceptibility gene. , 2010, Journal of Alzheimer's disease : JAD.

[32]  M. Michikawa,et al.  Apolipoprotein E4 (1–272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells , 2009, Molecular Neurodegeneration.

[33]  N. Filippini,et al.  Distinct patterns of brain activity in young carriers of the APOE e4 allele , 2009, NeuroImage.

[34]  P. Puigserver,et al.  AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity , 2009, Nature.

[35]  Gerard Manning,et al.  TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. , 2009, Cancer research.

[36]  W. Minor,et al.  Phosphorylation Regulates SIRT1 Function , 2008, PloS one.

[37]  M. McBurney,et al.  SirT1 Regulates Energy Metabolism and Response to Caloric Restriction in Mice , 2008, PloS one.

[38]  Jim Mintz,et al.  Apolipoprotein E Affects Both Myelin Breakdown and Cognition: Implications for Age-Related Trajectories of Decline Into Dementia , 2007, Biological Psychiatry.

[39]  W. C. Hallows,et al.  Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases , 2006, Proceedings of the National Academy of Sciences.

[40]  Jim Mintz,et al.  Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. , 2006, Archives of general psychiatry.

[41]  C. Adessi,et al.  A 13 kDa carboxy‐terminal fragment of ApoE stabilizes Abeta hexamers , 2005, Journal of neurochemistry.

[42]  S Minoshima,et al.  Cerebral glucose metabolism in patients with AD and different APOE genotypes , 2005, Neurology.

[43]  Kewei Chen,et al.  Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  D. Perani,et al.  MCI conversion to dementia and the APOE genotype , 2004, Neurology.

[45]  K. Herholz,et al.  Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer’s disease , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[46]  I. Santana,et al.  Cytochrome c oxidase is decreased in Alzheimer’s disease platelets , 2004, Neurobiology of Aging.

[47]  Gabriele Siciliano,et al.  Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease , 2002, Neurobiology of Aging.

[48]  C. Thompson,et al.  Pathways of Apoptosis in Lymphocyte Development, Homeostasis, and Disease , 2002, Cell.

[49]  C. Thompson,et al.  IL-7 Enhances the Survival and Maintains the Size of Naive T Cells1 , 2001, The Journal of Immunology.

[50]  David R. Plas,et al.  Growth Factors Can Influence Cell Growth and Survival through Effects on Glucose Metabolism , 2001, Molecular and Cellular Biology.

[51]  F Gonzalez-Lima,et al.  Energy Hypometabolism in Posterior Cingulate Cortex of Alzheimer's Patients: Superficial Laminar Cytochrome Oxidase Associated with Disease Duration , 2001, The Journal of Neuroscience.

[52]  M. V. Vander Heiden,et al.  In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. , 2000, Molecular cell.

[53]  M. V. Heiden,et al.  Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. , 1999, Molecular cell.

[54]  M. Trabucchi,et al.  Oxidative metabolism in cultured fibroblasts derived from sporadic Alzheimer's disease (AD) patients , 1997, Neuroscience Letters.

[55]  M. Beal,et al.  Cortical Cytochrome Oxidase Activity Is Reduced in Alzheimer's Disease , 1994, Journal of neurochemistry.

[56]  B. Hyman,et al.  Functional Alterations in Alzheimer's Disease: Selective Loss of Mitochondrial-encoded Cytochrome Oxidase mRNA in the Hippocampal Formation , 1994, Journal of neuropathology and experimental neurology.

[57]  S. Rapoport,et al.  Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease. , 1994, Brain research. Molecular brain research.

[58]  J. Nobrega,et al.  Brain Cytochrome Oxidase in Alzheimer's Disease , 1992, Journal of neurochemistry.

[59]  T. Dexter,et al.  Effect of haematopoietic cell growth factor on intracellular ATP levels , 1983, Nature.