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Neurobiol Aging. 2014 Jan;35(1):169-78. doi: 10.1016/j.neurobiolaging.2013.07.019. Epub 2013 Aug 21.

Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer's disease mouse model.

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  • 1Department 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.

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.

KEYWORDS:

Age-related Alzheimer's disease; Aging; Insulin/IGF-1 signaling; Klotho; Ligustilide; Memory deficits; Neuroprotection; Oxidative stress

PMID:
23973442
[PubMed - indexed for MEDLINE]
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