Neuroprotective effect of ligustilide through induction of α-secretase processing of both APP and klotho in a mouse model of Alzheimer’s disease


BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2017
Contact PI Name:
Jun-Rong Du
Contact PI Affiliation:
Key Laboratory of Drug Targeting and Drug Delivery System, Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, China
Co-Authors:
Xi Kuang, Hong-Jing Zhou, Amy H. Thorne, Xi-Nan Chen, Lin-Jiao Li
Primary Reference (PubMED ID):
Funding Source:
National Science Foundation of China
Study Goal and Principal Findings:

Emerging evidence suggests that alpha-processing single transmembrane proteins, amyloid precursor protein (APP) and anti-aging protein Klotho, are likely to be involved in the progression of Alzheimer’s disease (AD). The natural phthalide Ligustilide (LIG) has been demonstrated to protect against aging- and amyloid-β (Aβ)-induced brain dysfunction in animal models. The present study is to investigate the effects of LIG on cognitive deficits and metabolism of both APP and Klotho and its underlying mechanism in AD double-transgenic (APP/PS1) mice and cultured human cells. Our results show that treatment with LIG significantly ameliorated memory impairment and Aβ levels and plaques burden. Specifically, LIG might act as a potent enhancer of α-secretase, disintegrin, and metalloprotease 10 (ADAM10), leading to upregulation of alpha-processing of both APP and Klotho and subsequent increases in the levels of both soluble APP fragment (sAPPα) and soluble Klotho (sKL) with inhibition of IGF-1/Akt/mTOR signaling in AD mice and cultured cells. Moreover, the specific ADAM10 inhibitor (G1254023X) effectively reversed LIG-induced alpha-processing of both APP and Klotho in vitro, while Klotho gene knockdown by small interfering RNA significantly blunted LIG-mediated inhibition of IGF-1/Akt/mTOR signaling in vitro. Taken together with the reported neuroprotective effects of both sAPPα and sKL as well as autophagy induction by Akt/mTOR pathway inhibition, our findings suggest that neuroprotection of LIG against AD is associated with induction alpha-processing of APP and Klotho and potential Aβ clearance. Whether LIG might induce Aβ autophagic clearance and the underlying mechanisms need to be further studied.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Natural Product
Therapeutic Agent:
Ligustilide
Therapeutic Target:
Multi Target

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1
Strain/Genetic Background:
C57BL/6

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Passive Avoidance Test
Spontaneous Alternation
Y Maze
Histopathology
beta Amyloid Deposits
Neuronal Loss
Biochemical
alpha Secretase Activity
A Disintegrin and Metalloproteinase Domain 10 (ADAM10) mRNA
A Disintegrin and Metalloproteinase Domain 17 (ADAM17) mRNA
Amyloid Precursor Protein (APP) mRNA
Soluble Amyloid Precursor Protein alpha (sAPP alpha)
Protein Kinase B (Akt/PKB)
phospho-Protein Kinase B (phospho-Akt/PKB)
Insulin-Like Growth Factor 1 Receptor (IGF1R)
phospho-Insulin-Like Growth Factor 1 Receptor (phospho-IGF1R)
Mechanistic Target of Rapamycin (mTOR)
phospho-Mechanistic Target of Rapamycin (phospho-mTOR)
Klotho mRNA
Soluble Klotho
Brain-Guanidine Insoluble beta Amyloid Peptide 40
Brain-Guanidine Insoluble beta Amyloid Peptide 42
Brain-Guanidine Soluble beta Amyloid Peptide 40
Brain-Guanidine Soluble beta Amyloid Peptide 42
Immunochemistry
Amyloid Precursor Protein (APP)
Brain-beta Amyloid Deposits
Brain-beta Amyloid Peptide 42
Klotho
Neuronal Marker NeuN
Cell Biology
Cell Viability
Toxicology
Body Weight

Source URL: http://alzped.nia.nih.gov/neuroprotective-effect-0