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Leptin inhibits amyloid β-protein degradation through decrease of neprilysin expression in primary cultured
Naoki Yamamoto1, Mamoru Tanida2, Yoko Ono3
1Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa 920-1181, Japan; Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan.
Biochemical and Biophysical Research Communications
|February 11, 2014
Summary
Leptin, a hormone linked to Alzheimer's disease (AD) risk, was found to decrease amyloid-beta (Aβ) clearance by suppressing neprilysin (NEP) in brain cells. This suggests a novel mechanism linking leptin signaling to AD pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) pathogenesis involves amyloid-beta (Aβ) accumulation in the brain.
- Aβ levels are regulated by production and degradation, with neprilysin (NEP) and insulin-degrading enzyme (IDE) being key Aβ-degrading enzymes.
- Epidemiological studies suggest an inverse correlation between leptin levels and AD onset, but the underlying mechanisms are unclear.
Purpose of the Study:
- To investigate the association between leptin and Aβ degradation.
- To determine if leptin influences the expression of NEP and IDE in astrocytes.
Main Methods:
- Primary cultured rat astrocytes were treated with leptin.
- NEP and IDE expression levels were measured.
- Aβ degradation assays were performed.
- Extracellular signal-regulated kinase (ERK) activation was assessed.
Main Results:
- Leptin significantly decreased NEP expression in a concentration- and time-dependent manner.
- Leptin did not affect IDE expression.
- Leptin inhibited the degradation of exogenous Aβ in cultured astrocytes.
- Leptin-induced suppression of NEP was mediated by ERK activation.
Conclusions:
- Leptin suppresses Aβ degradation by inhibiting NEP expression through ERK activation.
- This finding provides a potential molecular mechanism linking leptin to Alzheimer's disease pathogenesis.
- Targeting leptin signaling or NEP activity could be a therapeutic strategy for AD.
