Obesity-related leptin regulates Alzheimer's Abeta

Abeta peptide is the major proteinateous component of the amyloid plaques found in the brains of Alzheimer's disease (AD) patients and is regarded by many as the culprit of the disorder. It is well documented that brain lipids are intricately involved in Abeta-related pathogenic pathways. An im...

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Bibliographic Details
Published in:The FASEB journal 2004-12, Vol.18 (15), p.1870-1878
Main Authors: Fewlass, Darius C, Noboa, Karina, Pi-Sunyer, F Xavier, Johnston, Jane M, Yan, Shi D, Tezapsidis, Nikolaos
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - genetics
Animals
CCAAT-Enhancer-Binding Proteins - physiology
Cells, Cultured
DNA-Binding Proteins - physiology
Humans
Leptin - pharmacology
Membrane Microdomains - drug effects
Membrane Microdomains - metabolism
Mice
Mice, Transgenic
Neurons - drug effects
Neurons - metabolism
Obesity - etiology
Peptide Fragments - metabolism
Rats
Sterol Regulatory Element Binding Protein 1
Sterol Regulatory Element Binding Protein 2
Transcription Factors - physiology
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Summary:Abeta peptide is the major proteinateous component of the amyloid plaques found in the brains of Alzheimer's disease (AD) patients and is regarded by many as the culprit of the disorder. It is well documented that brain lipids are intricately involved in Abeta-related pathogenic pathways. An important modulator of lipid homeostasis is the pluripotent peptide leptin. Here we demonstrate leptin's ability to modify Abeta levels in vitro and in vivo. Similar to methyl-beta-cyclodextrin, leptin reduces beta-secretase activity in neuronal cells possibly by altering the lipid composition of membrane lipid rafts. This phenotype contrasts treatments with cholesterol and etomoxir, an inhibitor of carnitine-palmitoyl transferase-1. Conversely, inhibitors of acetyl CoA carboxylase and fatty acid synthase mimicked leptin's action. Leptin was also able to increase apoE-dependent Abeta uptake in vitro. Thus, leptin can modulate bidirectional Abeta kinesis, reducing its levels extracellularly. Most strikingly, chronic administration of leptin to AD-transgenic animals reduced the brain Abeta load, underlying its therapeutic potential.
ISSN:0892-6638
1530-6860