1. Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer's disease mouse model.
- Author
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Kuang X, Chen YS, Wang LF, Li YJ, Liu K, Zhang MX, Li LJ, Chen C, He Q, Wang Y, and Du JR
- Subjects
- 4-Butyrolactone pharmacology, 4-Butyrolactone therapeutic use, Alzheimer Disease drug therapy, Amyloid beta-Peptides metabolism, Animals, Brain metabolism, Cells, Cultured, Disease Models, Animal, Forkhead Box Protein O1, Forkhead Transcription Factors metabolism, Glucuronidase metabolism, Insulin-Like Growth Factor I physiology, Klotho Proteins, Male, Memory Disorders genetics, Memory Disorders prevention & control, Mice, Mice, Inbred Strains, Molecular Targeted Therapy, Oxidative Stress genetics, Oxidative Stress physiology, Peptide Fragments metabolism, Phosphorylation drug effects, Signal Transduction drug effects, Signal Transduction genetics, Signal Transduction physiology, Up-Regulation drug effects, tau Proteins metabolism, 4-Butyrolactone analogs & derivatives, Aging genetics, Alzheimer Disease genetics, Alzheimer Disease prevention & control, Gene Expression Regulation, Developmental drug effects, Gene Expression Regulation, Developmental genetics, Glucuronidase genetics, Neuroprotective Agents
- Abstract
Klotho, an aging-suppressor gene, encodes a protein that potentially acts as a neuroprotective factor by modulating insulin-like growth factor 1 signaling and oxidative stress. In the present study, we investigated the potential role of Klotho in the therapeutic effect of ligustilide against Alzheimer's disease (AD)-like neuropathologies and memory impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. Ligustilide treatment (10 and 40 mg/kg for 8 weeks, intragastrically) in 10-month-old SAMP8 mice reduced memory deficits, amyloid-β(1)-42 accumulation, tau phosphorylation, and neuron loss, increased mitochondrial manganese-superoxide dismutase and catalase expression and activity, and decreased malondialdehyde, protein carbonyl, and 8-hydroxydesoxyguanosine levels in the brain. Ligustilide upregulated Klotho expression in the cerebral choroid plexus and serum, decreased Akt and Forkhead box class O1 phosphorylation. Moreover, ligustilide inhibited the insulin-like growth factor 1 pathway and induced Forkhead box class O1 activation in 293T cells along with Klotho upregulation. An inverse correlation was found between Klotho expression and the AD phenotype, suggesting that Klotho might be a novel therapeutic target for age-related AD, and Klotho upregulation might contribute to the neuroprotective effect of ligustilide against AD., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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