title: Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.
abstract: Alzheimer's disease (AD) is the most common type of dementia among the elderly. Neurofibrillary tangles (NFTs), a major pathological hallmark of AD, are composed of tau protein that is hyperphosphorylated by cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK3β). NFTs also contain Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) and collapsin response-mediator protein 2 (CRMP2). Although Cdk5 is known to phosphorylate tau, WAVE1, and CRMP2, the significance of this with respect to NFT formation remains to be elucidated. This study examines the involvement of phosphorylated (p-) CRMP2 and WAVE1 in p-tau aggregates using a triple-transgenic (3×Tg; APPswe/PS1M146V/tauP301L) AD mouse model. First, we verified the colocalization of p-WAVE1 and p-CRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates. To test the significance of phosphorylation of these proteins further, we administered all-trans-retinoic acid (ATRA) to the 3×Tg mice, which downregulates Cdk5 and GSK3β activity. In ATRA-treated mice, fewer and smaller tau aggregates were observed compared with non-ATRA-treated mice. These results suggest the possibility of novel therapeutic target molecules for preventing tau pathology.
authors.affiliation: Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Watamura
authors.affiliation: Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Toba
authors.affiliation: Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yoshii
authors.affiliation: Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.
authors.forename: Miyu
authors.initials: M
authors.lastname: Nikkuni
authors.affiliation: Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001583:Benzoxazoles / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics; D014212:Tretinoin / Q000627:therapeutic use*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C485711:6-(2-fluoroethoxy)-2-(2-(4-methylaminophenil)ethenyl)benzoxazole; C491049:Aif1 protein, mouse; D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; D014150:Antipsychotic Agents; D001583:Benzoxazoles; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D051300:Wiskott-Aldrich Syndrome Protein Family; C095114:collapsin response mediator protein-2; D016875:tau Proteins; D014212:Tretinoin; D051360:Cyclin-Dependent Kinase 5
keywords: ATRA; Alzheimer's disease; CRMP2; WAVE1; neurofibrillary tangle; tau