title: PPARγ agonist pioglitazone improves cerebellar dysfunction at pre-Aβ deposition stage in APPswe/PS1dE9 Alzheimer's disease model mice.
abstract: Alzheimer's disease (AD) is one of the best known neurodegenerative diseases; it causes dementia and its pathological features include accumulation of amyloid β (Aβ) and neurofibrillary tangles (NFTs) in the brain. Elevated Cdk5 activity and CRMP2 phosphorylation have been reported in the brains of AD model mice at the early stage of the disease, but the significance thereof in human AD remains unelucidated. We have recently reported that Aβ accumulation in the cerebellum of AD model APPswe/PS1dE9 (APP/PS1) mice, and cerebellar dysfunctions, such as impairment of motor coordination ability and long-term depression (LTD) induction, at the pre-Aβ accumulation stage. In the present study, we found increased phosphorylation levels of CRMP2 as well as increased p35 protein levels in the cerebellum of APP/PS1 mice. Interestingly, we show that pioglitazone, an agonist of peroxisome proliferator-activated receptor γ, normalized the p35 protein and CRMP2 phosphorylation levels in the cerebellum. Impaired motor coordination ability and LTD in APP/PS1 mice were ameliorated by pioglitazone treatment at the pre-Aβ accumulation stage. These results suggest a correlation between CRMP2 phosphorylation and AD pathophysiology, and indicate the effectiveness of pioglitazone treatment at the pre-Aβ accumulation stage in AD model mice.
authors.affiliation: Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Toba
authors.affiliation: Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan.
authors.forename: Miyu
authors.initials: M
authors.lastname: Nikkuni
authors.affiliation: Laboratory for Neurophysiology, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Ishizeki
authors.affiliation: Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yoshii
authors.affiliation: Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Watamura
authors.affiliation: Laboratory for Neurophysiology, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan. Electronic address: ohshima@waseda.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002526:Cerebellar Diseases / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D010770:Phosphotransferases / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; C492236:Cdk5r1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; C095114:collapsin response mediator protein-2; D010770:Phosphotransferases; D000077205:Pioglitazone
keywords: Alzheimer's disease; CRMP; Cerebellum; Mouse; Protein phosphorylation