ABSTRACT
Alzheimer's disease (AD) is one of the best known neurodegenerative diseases; it causes dementia and its pathological features include accumulation of amyloid ß (Aß) 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 Aß 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-Aß 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-Aß accumulation stage. These results suggest a correlation between CRMP2 phosphorylation and AD pathophysiology, and indicate the effectiveness of pioglitazone treatment at the pre-Aß accumulation stage in AD model mice.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Cerebellar Diseases/drug therapy , Cerebellar Diseases/physiopathology , Thiazolidinediones/administration & dosage , Alzheimer Disease/complications , Animals , Cerebellar Diseases/complications , Intercellular Signaling Peptides and Proteins , Male , Mice , Mice, Transgenic , Nerve Tissue Proteins/metabolism , PPAR gamma/antagonists & inhibitors , Phosphotransferases/metabolism , Pioglitazone , Treatment OutcomeABSTRACT
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 3ß (GSK3ß). 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 GSK3ß 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.
Subject(s)
Alzheimer Disease/drug therapy , Antipsychotic Agents/therapeutic use , Cyclin-Dependent Kinase 5/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Nerve Tissue Proteins/metabolism , Tretinoin/therapeutic use , Wiskott-Aldrich Syndrome Protein Family/metabolism , tau Proteins/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , Aniline Compounds/metabolism , Animals , Benzoxazoles/metabolism , Calcium-Binding Proteins/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Humans , Mice , Mice, Transgenic , Microfilament Proteins/metabolism , Neurites/metabolism , Neurites/pathology , Neurons/metabolism , Phosphorylation/physiology , Presenilin-1/genetics , tau Proteins/geneticsABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder that represents the most common type of dementia among elderly people. Amyloid beta (Aß) peptides in extracellular Aß plaques, produced from the amyloid precursor protein (APP) via sequential processing by ß- and γ-secretases, impair hippocampal synaptic plasticity, and cause cognitive dysfunction in AD patients. Here, we report that Aß peptides also impair another form of synaptic plasticity; cerebellar long-term depression (LTD). In the cerebellum of commonly used AD mouse model, APPswe/PS1dE9 mice, Aß plaques were detected from 8 months and profound accumulation of Aß plaques was observed at 18 onths of age. Biochemical analysis revealed relatively high levels of APP protein and Aß in the cerebellum of APPswe/PS1dE9 mice. At pre-Aß accumulation stage, LTD induction, and motor coordination are disturbed. These results indicate that soluble Aß oligomers disturb LTD induction and cerebellar function in AD mouse model.
