title: Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer's disease mouse model.
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.
authors: Department of Pharmacology, Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of Education, West China School of Pharmacy, and Translational Neuroscience Center, Sichuan University, Chengdu, China.
authors: Xi
authors: X
authors: Kuang
authors: Ya-Shu
authors: YS
authors: Chen
authors: Liang-Fen
authors: LF
authors: Wang
authors: Yong-Jie
authors: YJ
authors: Li
authors: Ke
authors: K
authors: Liu
authors: Meng-Xue
authors: MX
authors: Zhang
authors: Ling-Jiao
authors: LJ
authors: Li
authors: Chu
authors: C
authors: Chen
authors: Qian
authors: Q
authors: He
authors: Yu
authors: Y
authors: Wang
authors: Jun-Rong
authors: JR
authors: Du
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects* / Q000235:genetics*; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D000090265:Klotho Proteins; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000517:prevention & control; D051379:Mice; D008815:Mice, Inbred Strains; D058990:Molecular Targeted Therapy; D018696:Neuroprotective Agents; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D016875:tau Proteins; C027820:ligustilide; D007334:Insulin-Like Growth Factor I; D005966:Glucuronidase; D000090265:Klotho Proteins; D015107:4-Butyrolactone
keywords: Age-related Alzheimer's disease; Aging; Insulin/IGF-1 signaling; Klotho; Ligustilide; Memory deficits; Neuroprotection; Oxidative stress