Obesity‐related leptin regulates Alzheimer's Aβ

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Abstract
Aβ 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 Aβ-related pathogenic pathways. An important modulator of lipid homeostasis is the pluripotent peptide leptin. Here we demonstrate leptin’s ability to modify Aβ levels in vitro and in vivo. Similar to methyl-β-cyclodextrin, leptin reduces β-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 Aβ uptake in vitro. Thus, leptin can modulate bidirectional Aβ kinesis, reducing its levels extracellularly. Most strikingly, chronic administration of leptin to AD-transgenic animals reduced the brain Aβ load, underlying its therapeutic potential.—Fewlass, D. C., Noboa, K., Pi-Sunyer, F. X., Johnston, J. M., Yan, S. D., Tezapsidis, N. Obesity-related leptin regulates Alzheimer’s Aβ.