An aberrant protein complex in CSF as a biomarker of Alzheimer disease

Objective: To determine if an aberrant protein complex consisting of prostaglandin-d-synthase (PDS) and transthyretin (TTR) in CSF differentiates between subjects with Alzheimer disease (AD) and normal control (NC) subjects. Methods: Western blot analysis and a unique sandwich ELISA were used to quantify levels of complexed PDS/TTR in ventricular CSF of subjects with autopsy-verified diagnoses and in lumbar CSF of living subjects with mild to moderate probable AD and age-matched NC subjects. Ventricular CSF was obtained from short postmortem interval autopsies of 7 NC subjects (4 men/3 women), 12 diseased control (DC) subjects (7 men/5 women), 4 subjects with mild cognitive impairment (MCI) (2 men/2 women), and 8 subjects with late-stage AD (LAD) (4 men/4 women). Lumbar CSF was obtained from 15 subjects with probable AD (5 men/10 women) and 14 age-matched NC subjects (10 men/4 women) and was analyzed in a double-blind fashion. Results: A significant increase in complexed PDS/TTR in ventricular CSF was found in MCI and LAD subjects but not DC subjects compared with NC subjects. Double-blind analysis of complexed PDS/TTR in lumbar CSF showed a significant sixfold increase in levels of the PDS/TTR complex in living probable AD subjects compared with age-matched NC subjects and a 100% sensitivity and 93% specificity in the identification of subjects with AD. Conclusion: After further study of larger numbers of patients, quantifying prostaglandin-d-synthase/transthyretin complex in CSF may be useful in the diagnosis of Alzheimer disease, possibly in the early stages of the disease.

[1]  J. Clausen.  Proteins in Normal Cerebrospinal Fluid Not Found in Serum.∗ , 1961, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[2]  W. Elliott,et al.  Transport of thyroid hormones in serum and cerebrospinal fluid. , 1973, The Journal of clinical endocrinology and metabolism.

[3]  R. Canfield,et al.  The amino acid sequence of human plasma prealbumin. , 1974, The Journal of biological chemistry.

[4]  E. Christ-Hazelhof,et al.  Purification and characterisation of prostaglandin endoperoxide D-isomerase, a cytoplasmic, glutathione-requiring enzyme. , 1979, Biochimica et biophysica acta.

[5]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[6]  G. Howlett,et al.  Rat transthyretin (prealbumin). Molecular cloning, nucleotide sequence, and gene expression in liver and brain. , 1985, The Journal of biological chemistry.

[7]  H. Toh,et al.  Human brain prostaglandin D synthase has been evolutionarily differentiated from lipophilic-ligand carrier proteins. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Liepnieks,et al.  Production and functional analysis of normal and variant recombinant human transthyretin proteins. , 1992, The Journal of biological chemistry.

[9]  W. Strittmatter,et al.  Transthyretin sequesters amyloid beta protein and prevents amyloid formation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[10]  V. Young,et al.  Transthyretin (prealbumin) in health and disease: nutritional implications. , 1994, Annual review of nutrition.

[11]  Y. Urade,et al.  Prostaglandin D, E, and F synthases. , 1995, Journal of lipid mediators and cell signalling.

[12]  B. Silvestrini,et al.  Astrocytes synthesize and secrete prostaglandin D synthetase in vitro. , 1996, Biochimica et biophysica acta.

[13]  John Q. Trojanowski,et al.  Consensus Recommendations for the Postmortem Diagnosis of Alzheimer’s Disease , 1997, Neurobiology of Aging.

[14]  T. Yamashima,et al.  Prostaglandin D Synthase (β-Trace) in Human Arachnoid and Meningioma Cells: Roles as a Cell Marker or in Cerebrospinal Fluid Absorption, Tumorigenesis, and Calcification Process , 1997, The Journal of Neuroscience.

[15]  D. Christmann,et al.  Cerebrospinal fluid transthyretin: aging and late onset Alzheimer’s disease , 1997, Journal of neurology, neurosurgery, and psychiatry.

[16]  R. Kikuno,et al.  Cloning and Crystal Structure of Hematopoietic Prostaglandin D Synthase , 1997, Cell.

[17]  W. Markesbery,et al.  Four-Hydroxynonenal, a Product of Lipid Peroxidation, is Increased in the Brain in Alzheimer’s Disease , 1998, Neurobiology of Aging.

[18]  G. Siest,et al.  Apolipoprotein E, transthyretin and actin in the CSF of Alzheimer's patients: relation with the senile plaques and cytoskeleton biochemistry , 1998, FEBS letters.

[19]  M. Saraiva,et al.  The Tetrameric Protein Transthyretin Dissociates to a Non-native Monomer in Solution , 1999, The Journal of Biological Chemistry.

[20]  E. Tangalos,et al.  Mild Cognitive Impairment Clinical Characterization and Outcome , 1999 .

[21]  Y. Ando,et al.  Impact of age and amyloidosis on thiol conjugation of transthyretin in hereditary transthyretin amyloidosis. , 1999, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[22]  S. Uemoto,et al.  VARIANT TRANSTHYRETIN IN BLOOD CIRCULATION CAN TRANSVERSE THE BLOOD-CEREBROSPINAL BARRIER: QUALITATIVE ANALYSES OF TRANSTHYRETIN METABOLISM IN SEQUENTIAL LIVER TRANSPLANTATION1 , 2001, Transplantation.

[23]  Rui M. M. Brito,et al.  Tetramer Dissociation and Monomer Partial Unfolding Precedes Protofibril Formation in Amyloidogenic Transthyretin Variants* , 2001, The Journal of Biological Chemistry.

[24]  M. Saraiva.  Transthyretin amyloidosis: a tale of weak interactions , 2001, FEBS letters.

[25]  Y. Urade,et al.  Perineuronal Oligodendrocytes Protect against Neuronal Apoptosis through the Production of Lipocalin-Type Prostaglandin D Synthase in a Genetic Demyelinating Model , 2002, The Journal of Neuroscience.

[26]  A. Sickmann,et al.  Towards a high resolution separation of human cerebrospinal fluid. , 2002, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[27]  Y. Urade,et al.  Prostaglandin D2 in Sleep-Wake Regulation: Recent Progress and Perspectives , 2002, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[28]  Giampaolo Merlini,et al.  Molecular mechanisms of amyloidosis. , 2003, The New England journal of medicine.

[29]  C. DeCarli,et al.  Neutralization of Transthyretin Reverses the Neuroprotective Effects of Secreted Amyloid Precursor Protein (APP) in APPSw Mice Resulting in Tau Phosphorylation and Loss of Hippocampal Neurons: Support for the Amyloid Hypothesis , 2004, The Journal of Neuroscience.

[30]  S. Sakoda,et al.  Modification of cysteine residue in transthyretin and a synthetic peptide: analyses by electrospray ionization mass spectrometry. , 2004, Biochimica et biophysica acta.

[31]  J. Kelly,et al.  Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[32]  T. Montine,et al.  F2-isoprostanes in Alzheimer and other neurodegenerative diseases. , 2005, Antioxidants & redox signaling.

[33]  P. Lescuyer,et al.  Prostaglandin D2 synthase and its post‐translational modifications in neurological disorders , 2005, Electrophoresis.

[34]  A. Fonteh,et al.  Prostaglandin D Synthase Isoforms from Cerebrospinal Fluid Vary with Brain Pathology , 2005, Disease markers.

[35]  Charles D. Smith,et al.  Neuropathologic substrate of mild cognitive impairment. , 2006, Archives of neurology.

[36]  W. Markesbery,et al.  Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer's disease , 2006, Neurobiology of Aging.

[37]  G. Bernardi,et al.  Differential post‐translational modifications of transthyretin in Alzheimer's disease: A study of the cerebral spinal fluid , 2006, Proteomics.

[38]  M. Sjögren,et al.  Proteome studies of CSF in AD patients , 2006, Mechanisms of Ageing and Development.

[39]  Norman Relkin,et al.  Cerebrospinal fluid proteomic biomarkers for Alzheimer's disease , 2007, Annals of neurology.