Faulty regulation of tau phosphorylation by the reelin signal transduction pathway is a potential mechanism of pathogenesis and therapeutic target in Alzheimer's disease

Hyperphosphorylated tau protein is the basic structural component of the neurofibrillary tangle, a histopathological hallmark of Alzheimer's disease. The formation of hyperphosphorylated tau protein may impair learning and the synaptic plasticity of neurons. Tau is a protein that is associated with and stabilizes microtubules; hyperphosphorylated tau protein is unable to perform this stabilization function. The transduction of reelin, a protein that is crucial to neuronal migration and the formation of synaptic connections in the fetal brain, may have an equally important role in regulating at least some forms of learning and synaptic plasticity in the fully developed mature brain. Reelin transduction is mediated by receptors in the brain that are members of the superfamily of low-density lipoprotein receptors. An important downstream target of reelin signal transduction appears to be inhibition of an enzyme involved in the regulation of tau phosphorylation. The faulty transduction of the reelin signal may be a pathological mechanism leading to hyperphosphorylation of tau protein. Ultimately, inhibition of tau phosphorylation may be an important therapeutic target in Alzheimer's disease and other neuropsychiatric disorders.

[1]  Jesús Avila,et al.  Glycogen synthase kinase 3: a drug target for CNS therapies , 2004, Journal of neurochemistry.

[2]  H. Paudel,et al.  Glycogen Synthase Kinase-3β Is Complexed with Tau Protein in Brain Microtubules* , 2002, The Journal of Biological Chemistry.

[3]  A. Guidotti,et al.  REELIN and schizophrenia: a disease at the interface of the genome and the epigenome. , 2002, Molecular interventions.

[4]  V. Lee,et al.  Insulin and Insulin-like Growth Factor-1 Regulate Tau Phosphorylation in Cultured Human Neurons* , 1997, The Journal of Biological Chemistry.

[5]  M. Vitek,et al.  Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an Apolipoprotein E receptor/disabled‐1/glycogen synthase kinase‐3β cascade , 2003 .

[6]  T. Curran,et al.  Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS. , 1999, Genes & development.

[7]  E. Costa,et al.  Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[8]  John Shelton,et al.  Reeler/Disabled-like Disruption of Neuronal Migration in Knockout Mice Lacking the VLDL Receptor and ApoE Receptor 2 , 1999, Cell.

[9]  I. Tesseur,et al.  Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. , 2000, The American journal of pathology.

[10]  Virginia M. Y. Lee,et al.  Lithium Reduces Tau Phosphorylation by Inhibition of Glycogen Synthase Kinase-3* , 1997, The Journal of Biological Chemistry.

[11]  Joachim Herz,et al.  Reelin Activates Src Family Tyrosine Kinases in Neurons , 2003, Current Biology.

[12]  A. Guidotti,et al.  The heterozygote reeler mouse as a model for the development of a new generation of antipsychotics. , 2002, Current opinion in pharmacology.

[13]  W. Schneider,et al.  LDL receptor relatives at the crossroad of endocytosis and signaling , 2003, Cellular and Molecular Life Sciences CMLS.

[14]  Joachim Herz,et al.  Direct Binding of Reelin to VLDL Receptor and ApoE Receptor 2 Induces Tyrosine Phosphorylation of Disabled-1 and Modulates Tau Phosphorylation , 1999, Neuron.

[15]  Ramin Homayouni,et al.  Reelin Is a Ligand for Lipoprotein Receptors , 1999, Neuron.

[16]  T. Curran,et al.  Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1. , 2003, Brain research. Molecular brain research.

[17]  A. Guidotti,et al.  Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice , 2005, Biological Psychiatry.

[18]  Jonathan A. Cooper,et al.  Lipoprotein Receptors Signaling Functions in the Brain? , 1999, Cell.

[19]  J. Sweatt,et al.  Reelin and ApoE Receptors Cooperate to Enhance Hippocampal Synaptic Plasticity and Learning* , 2002, The Journal of Biological Chemistry.

[20]  Yogesh K. Dwivedi,et al.  Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. , 2000, Archives of general psychiatry.