Transthyretin (TTR), a carrier protein present in the liver and choroid plexus of the brain, has been shown to be responsible for binding thyroid hormone thyroxin (T4) and retinol in plasma and cerebrospinal fluid (CSF). TTR aids in sequestering of beta-amyloid peptides Aβ deposition, and protects the brain from trauma, ischemic stroke and Alzheimer disease (AD). Accordingly, hippocampal gene expression of TTR plays a significant role in learning and memory as well as in simulation of spatial memory tasks. TTR via interacting with transcription factor CREB regulates this process and decreased expression leads to memory deficits. By different signaling pathways, like MAPK, AKT, and ERK via Src, TTR provides tropical support through megalin receptor by promoting neurite outgrowth and protecting the neurons from traumatic brain injury. TTR is also responsible for the transient rise in intracellular Ca2+ via NMDA receptor, playing a dominant role under excitotoxic conditions. In this review, we tried to shed light on how TTR is involved in maintaining normal cognitive processes, its role in learning and memory, under memory deficit conditions; by which mechanisms it promotes neurite outgrowth; and how it protects the brain from Alzheimer disease (AD).
Ribeiro, C.A., et al. (2014) Transthyretin Stabilization by Iododiflunisal Promotes Amyloid-Beta Peptide Clearance, Decreases Its Deposition, and Ameliorates Cognitive Deficits in an Alzheimer's Disease Mouse Model. Journal of Alzheimer’s Disease, 39, 357-370.
Bauer, M., Heinz, A. and Whybrow, P.C. (2002) Thyroid Hormones, Serotonin and Mood: Of Synergy and Significance in the Adult Brain. Molecular Psychiatry, 7, 140-156. https://doi.org/10.1038/sj.mp.4000963
Dickson, P.W. and Schreiber, G. (1986) High Levels of Messenger RNA for Transthyretin (Prealbumin) in Human Choroid Plexus. Neuroscience Letters, 66, 311-315. https://doi.org/10.1016/0304-3940(86)90037-6
Kassem, N.A., et al. (2006) Role of Transthyretin in Thyroxine Transfer from Cerebrospinal Fluid to Brain and Choroid Plexus. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 291, R1310-R1315. ps://doi.org/10.1152/ajpregu.00789.2005
Chen, R., Chen, C.P. and Preston, J.E. (2016) Effects of Transthyretin on Thyroxine and Beta-Amyloid Removal from Cerebrospinal Fluid in Mice. Clinical and Experimental Pharmacology & Physiology, 43, 844-850. https://doi.org/10.1111/1440-1681.12598
Suzuyama, K., et al. (2004) Combined Proteomic Approach with SELDI-TOF-MS and Peptide Mass Fingerprinting Identified the Rapid Increase of Monomeric Transthyretin in Rat Cerebrospinal Fluid after Transient Focal Cerebral Ischemia. Molecular Brain Research, 129, 44-53. https://doi.org/10.1016/j.molbrainres.2004.06.021
Schwarzman, A.L., et al. (1994) Transthyretin Sequesters Amyloid Beta Protein and Prevents Amyloid Formation. Proceedings of the National Academy of Sciences of the United States of America, 91, 8368-8372.
Schultz, K., Traskman-Bendz, L. and Petersen, A. (2008) Transthyretin in Cerebrospinal Fluid from Suicide Attempters. Journal of Affective Disorders, 109, 205-208. https://doi.org/10.1016/j.jad.2007.11.007
Alemi, M., et al. (2016) Transthyretin Participates in Beta-Amyloid Transport from the Brain to the Liver—Involvement of the Low-Density Lipoprotein Receptor-Related Protein 1? Scientific Reports, 6, Article Number: 20164. https://doi.org/10.1038/srep20164
Costa, R., et al. (2008) Transthyretin Protects against A-Beta Peptide Toxicity by Proteolytic Cleavage of the Peptide: A Mechanism Sensitive to the Kunitz Protease Inhibitor. PLoS ONE, 3, e2899. https://doi.org/10.1371/journal.pone.0002899
Alshehri, B., et al. (2015) The Diversity of Mechanisms Influenced by Transthyretin in Neurobiology: Development, Disease and Endocrine Disruption. Journal of Neuroendocrinology, 27, 303-323. https://doi.org/10.1111/jne.12271
Fleming, C.E., et al. (2009) Transthyretin Internalization by Sensory Neurons Is Megalin Mediated and Necessary for Its Neuritogenic Activity. Journal of Neuroscience, 29, 3220-3232. https://doi.org/10.1523/JNEUROSCI.6012-08.2009
Goncalves, N.P., Teixeira-Coelho, M. and Saraiva, M.J. (2015) Protective Role of Anakinra against Transthyretin-Mediated Axonal Loss and Cell Death in a Mouse Model of Familial Amyloidotic Polyneuropathy. Journal of Neuropathology & Experimental Neurology, 74, 203-217. https://doi.org/10.1097/NEN.0000000000000164
Doggui, S., et al. (2010) Possible Involvement of Transthyretin in Hippocampal Beta-Amyloid Burden and Learning Behaviors in a Mouse Model of Alzheimer’s Disease (TgCRND8). Neurodegenerative Diseases, 7, 88-95. https://doi.org/10.1159/000285513
Gomes, J.R., et al. (2016) Transthyretin Provides Trophic Support via Megalin by Promoting Neurite Outgrowth and Neuroprotection in Cerebral Ischemia. Cell Death and Differentiation, 23, 1749-1764. https://doi.org/10.1038/cdd.2016.64
Alvira-Botero, X., et al. (2010) Megalin Interacts with APP and the Intracellular Adapter Protein FE65 in Neurons. Molecular and Cellular Neuroscience, 45, 306-315. https://doi.org/10.1016/j.mcn.2010.07.005
Gao, C., et al. (2011) Serum Prealbumin (Transthyretin) Predict Good Outcome in Young Patients with Cerebral Infarction. Clinical and Experimental Medicine, 11, 49-54. https://doi.org/10.1007/s10238-010-0103-8
Sousa, M.M. and Saraiva, M.J. (2001) Internalization of Transthyretin. Evidence of a Novel yet Unidentified Receptor-Associated Protein (RAP)-Sensitive Receptor. The Journal of Biological Chemistry, 276, 14420-14425. https://doi.org/10.1074/jbc.M010869200
Sousa, M.M., et al. (2000) Interaction of the Receptor for Advanced Glycation End Products (RAGE) with Transthyretin Triggers Nuclear Transcription Factor kB (NF-kB) Activation. Laboratory Investigation, 80, 1101-1110. https://doi.org/10.1038/labinvest.3780116
Vieira, M., Gomes, J.R. and Saraiva, M.J. (2015) Transthyretin Induces Insulin-Like Growth Factor I Nuclear Translocation Regulating Its Levels in the Hippocampus. Molecular Neurobiology, 51, 1468-1479. https://doi.org/10.1007/s12035-014-8824-4
Marzolo, M.P. and Farfan, P. (2011) New Insights into the Roles of Megalin/LRP2 and the Regulation of Its Functional Expression. Biological Research, 44, 89-105. https://doi.org/10.4067/S0716-97602011000100012
Mantuano, E., et al. (2008) Molecular Dissection of the Human Alpha2-Macroglobulin Subunit Reveals Domains with Antagonistic Activities in Cell Signaling. The Journal of Biological Chemistry, 283, 19904-19911. https://doi.org/10.1074/jbc.M801762200
Lai, T.W., Zhang, S. and Wang, Y.T. (2014) Excitotoxicity and Stroke: Identifying Novel Targets for Neuroprotection. Progress in Neurobiology, 115, 157-188. https://doi.org/10.1016/j.pneurobio.2013.11.006
Hill, M.D., et al. (2012) Safety and Efficacy of NA-1 in Patients with Iatrogenic Stroke after Endovascular Aneurysm Repair (ENACT): A Phase 2, Randomised, Double-Blind, Placebo-Controlled Trial. The Lancet Neurology, 11, 942-950. https://doi.org/10.1016/S1474-4422(12)70225-9
Gonzalez-Marrero, I., et al. (2015) Choroid Plexus Dysfunction Impairs Beta-Amyloid Clearance in a Triple Transgenic Mouse Model of Alzheimer’s Disease. Frontiers in Cellular Neuroscience, 9, 17. https://doi.org/10.3389/fncel.2015.00017
Bach, M.E., et al. (1999) Age-Related Defects in Spatial Memory Are Correlated with Defects in the Late Phase of Hippocampal Long-Term Potentiation in vitro and Are Attenuated by Drugs That Enhance the cAMP Signaling Pathway. Proceedings of the National Academy of Sciences of the United States of America, 96, 5280-5285. https://doi.org/10.1073/pnas.96.9.5280
Tombaugh, G.C., et al. (2002) Theta-Frequency Synaptic Potentiation in CA1 in vitro Distinguishes Cognitively Impaired from Unimpaired Aged Fischer 344 Rats. The Journal of Neuroscience, 22, 9932-9940.
Brouillette, J. and Quirion, R. (2008) Transthyretin: A Key Gene Involved in the Maintenance of Memory Capacities during Aging. Neurobiology of Aging, 29, 1721-1732. https://doi.org/10.1016/j.neurobiolaging.2007.04.007
Misner, D.L., et al. (2001) Vitamin A Deprivation Results in Reversible Loss of Hippocampal Long-Term Synaptic Plasticity. Proceedings of the National Academy of Sciences of the United States of America, 98, 11714-11719. https://doi.org/10.1073/pnas.191369798
Etchamendy, N., et al. (2001) Alleviation of a Selective Age-Related Relational Memory Deficit in Mice by Pharmacologically Induced Normalization of Brain Retinoid Signaling. The Journal of Neuroscience, 21, 6423-6429.
Chen, A., et al. (2003) Inducible Enhancement of Memory Storage and Synaptic Plasticity in Transgenic Mice Expressing an Inhibitor of ATF4 (CREB-2) and C/EBP Proteins. Neuron, 39, 655-669. https://doi.org/10.1016/S0896-6273(03)00501-4
Mouravlev, A., et al. (2006) Somatic Gene Transfer of cAMP Response Element-Binding Protein Attenuates Memory Impairment in Aging Rats. Proceedings of the National Academy of Sciences of the United States of America, 103, 4705-4710. https://doi.org/10.1073/pnas.0506137103
Jacobs, S., et al. (2006) Retinoic Acid Is Required Early during Adult Neurogenesis in the Dentate Gyrus. Proceedings of the National Academy of Sciences of the United States of America, 103, 3902-3907. https://doi.org/10.1073/pnas.0511294103
von Bohlen und Halbach, O., et al. (2006) Age-Related Alterations in Hippocampal Spines and Deficiencies in Spatial Memory in Mice. Journal of Neuroscience Research, 83, 525-531. https://doi.org/10.1002/jnr.20759
Jacobsen, J.S., et al. (2006) Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 103, 5161-5166. https://doi.org/10.1073/pnas.0600948103
Lavado-Autric, R., et al. (2003) Early Maternal Hypothyroxinemia Alters Histogenesis and Cerebral Cortex Cytoarchitecture of the Progeny. The Journal of Clinical Investigation, 111, 1073-1082. https://doi.org/10.1172/JCI200316262
Gilbert, M.E. and Sui, L. (2006) Dose-Dependent Reductions in Spatial Learning and Synaptic Function in the Dentate Gyrus of Adult Rats Following Developmental Thyroid Hormone Insufficiency. Brain Research, 1069, 10-22. https://doi.org/10.1016/j.brainres.2005.10.049
Benoit, C.E., et al. (2011) Genomic and Proteomic Strategies to Identify Novel Targets Potentially Involved in Learning and Memory. Trends in Pharmacological Sciences, 32, 43-52. https://doi.org/10.1016/j.tips.2010.10.002
Thorsell, A., et al. (2000) Behavioral Insensitivity to Restraint Stress, Absent Fear Suppression of Behavior and Impaired Spatial Learning in Transgenic Rats with Hippocampal Neuropeptide Y Overexpression. Proceedings of the National Academy of Sciences of the United States of America, 97, 12852-12857. https://doi.org/10.1073/pnas.220232997
Schindler, C.K., Heverin, M. and Henshall, D.C. (2006) Isoform- and Subcellular Fraction-Specific Differences in Hippocampal 14-3-3 Levels Following Experimentally Evoked Seizures and in Human Temporal Lobe Epilepsy. Journal of Neurochemistry, 99, 561-569. https://doi.org/10.1111/j.1471-4159.2006.04153.x
Pozuelo-Rubio, M. (2011) Regulation of Autophagic Activity by 14-3-3Zeta Proteins Associated with Class III Phosphatidylinositol-3-Kinase. Cell Death and Differentiation, 18, 479-492. https://doi.org/10.1038/cdd.2010.118
Rajawat, Y., Hilioti, Z. and Bossis, I. (2011) Retinoic Acid Induces Autophagosome Maturation through Redistribution of the Cation-Independent Mannose-6-Phosphate Receptor. Antioxidants & Redox Signaling, 14, 2165-2177. https://doi.org/10.1089/ars.2010.3491
Philibert, K.D., et al. (2014) Identification and Characterization of ABeta Peptide Interactors in Alzheimer’s Disease by Structural Approaches. Frontiers in Aging Neuroscience, 6, 265. https://doi.org/10.3389/fnagi.2014.00265
Crossgrove, J.S., Li, G.J. and Zheng, W. (2005) The Choroid Plexus Removes Beta-Amyloid from Brain Cerebrospinal Fluid. Experimental Biology and Medicine (Maywood), 230, 771-776. https://doi.org/10.1177/153537020523001011
Crossgrove, J.S., Smith, E.L. and Zheng, W. (2007) Macromolecules Involved in Production and Metabolism of Beta-Amyloid at the Brain Barriers. Brain Research, 1138, 187-195. https://doi.org/10.1016/j.brainres.2006.12.022
Tsai, K.J., et al. (2009) Asymmetric Expression Patterns of Brain Transthyretin in Normal Mice and a Transgenic Mouse Model of Alzheimer’s Disease. Neuroscience, 159, 638-646. https://doi.org/10.1016/j.neuroscience.2008.12.045
Merched, A., et al. (1998) Apolipoprotein E, Transthyretin and Actin in the CSF of Alzheimer’s Patients: Relation with the Senile Plaques and Cytoskeleton Biochemistry. FEBS Letters, 425, 225-228. https://doi.org/10.1016/S0014-5793(98)00234-8
Stein, T.D. and Johnson, J.A. (2002) Lack of Neurodegeneration in Transgenic Mice Overexpressing Mutant Amyloid Precursor Protein Is Associated with Increased Levels of Transthyretin and the Activation of Cell Survival Pathways. Journal of Neuroscience, 22, 7380-7388.
Serot, J.M., et al. (1997) Cerebrospinal Fluid Transthyretin: Aging and Late Onset Alzheimer’s disease. The Journal of Neurology, Neurosurgery, and Psychiatry, 63, 506-508. https://doi.org/10.1136/jnnp.63.4.506
Gloeckner, S.F., et al. (2008) Quantitative Analysis of Transthyretin, Tau and Amyloid-Beta in Patients with Dementia. The Journal of Alzheimer’s Disease, 14, 17-25. https://doi.org/10.3233/JAD-2008-14102
Hansson, S.F., et al. (2009) Reduced Levels of Amyloid-Beta-Binding Proteins in Cerebrospinal Fluid from Alzheimer’s Disease Patients. The Journal of Alzheimer’s Disease, 16, 389-397. https://doi.org/10.3233/JAD-2009-0966
Chodobski, A. and Szmydynger-Chodobska, J. (2001) Choroid Plexus: Target for Polypeptides and Site of Their Synthesis. Microscopy Research and Technique, 52, 65-82. https://doi.org/10.1002/1097-0029(20010101)52:1<65::AID-JEMT9>3.0.CO;2-4
Geroldi, C., et al. (2000) Temporal Lobe Asymmetry in Patients with Alzheimer’s Disease with Delusions. The Journal of Neurology, Neurosurgery, and Psychiatry, 69, 187-191. https://doi.org/10.1136/jnnp.69.2.187
Maetani, Y., et al. (2016) Familial Amyloid Polyneuropathy Involving a Homozygous Val30Met Mutation in the Amyloidogenic Transthyretin Gene Presenting with Superficial Siderosis: A Case Report. Rinsho Shinkeigaku, 56, 430-434.
Li, X. and Buxbaum, J.N. (2011) Transthyretin and the Brain Re-Visited: Is Neuronal Synthesis of Transthyretin Protective in Alzheimer’s Disease? Molecular Neurodegeneration, 6, 79. https://doi.org/10.1186/1750-1326-6-79
Dewachter, I., et al. (2000) Aging Increased Amyloid Peptide and Caused Amyloid Plaques in Brain of Old APP/V717I Transgenic Mice by a Different Mechanism than Mutant Presenilin1. Journal of Neuroscience, 20, 6452-6458.
Bergen, A.A., et al. (2015) Gene Expression and Functional Annotation of Human Choroid Plexus Epithelium Failure in Alzheimer’s Disease. BMC Genomics, 16, 956. https://doi.org/10.1186/s12864-015-2159-z
Bastianetto, S., Brouillette, J. and Quirion, R. (2007) Neuroprotective Effects of Natural Products: Interaction with Intracellular Kinases, Amyloid Peptides and a Possible Role for Transthyretin. Neurochemical Research, 32, 1720-1725. https://doi.org/10.1007/s11064-007-9333-x