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 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.
Fewlass
Darius C
DC
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Noboa
Karina
K
Pi-Sunyer
F Xavier
FX
Johnston
Jane M
JM
Yan
Shi D
SD
Tezapsidis
Nikolaos
N
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000209:etiology; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D020738:Leptin; D010446:Peptide Fragments; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors