Though there is already plenty of evidence linking lipid metabolism and obesity to Alzheimer disease (AD) and other neurodegenerative diseases (see, for example, ARF related news story and ARF news story), the case just got stronger. Reporting in the December FASEB Journal, Nikolaos Tezapsidis and colleagues at Columbia University’s Taub Institute for Research on AD in New York show that leptin can attenuate production of amyloid-β in vitro and in transgenic animal models of AD.
Leptin (from the Greek for thin) plays an enormously important role in controlling weight gain, and many us have indelibly etched in our minds the almost surreal picture of a normal mouse and a vastly bigger, leptin-deficient mouse standing side by side. Now, some 10 years after leptin was discovered, first author Darius Fewlass and colleagues focus on how the hormone may tilt the delicate balance that governs Aβ production in the CNS.
Fewlass and colleagues first investigated the effect of leptin on neuronal cells. When they treated neurons (Neuro2a cells) with leptin they found the hormone reduced β-secretase (BACE) activity, Aβ production, and cholesterol-stimulated increases in Aβ production. In addition, Fewlass and colleagues found that leptin also boosted uptake of Aβ by neurons, a process that was driven by ApoE in an isoform-dependent manner, ApoE4 being less efficient than the ApoE3 isoform.
Turning to the physiological relevance of these in vitro findings, the authors found that in mouse models of AD, plasma leptin levels were lower than in wild-type littermates. Importantly, they also found that administering leptin to PS1(M146V)/AβPP (KM670/671/NL Swedish) transgenic animals for two months reduces the amount of formic acid-extractable Aβ1-40 and Aβ1-42 in the brain by up to 50 percent. These results suggest that leptin may either directly, or indirectly through its effect on lipid metabolism, help abrogate AD pathology. (See more detailed description of the results below in the comment by Nikolaos Tezapsidis).—Tom Fagan
- Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N. Obesity-related leptin regulates Alzheimer's Abeta. FASEB J. 2004 Dec;18(15):1870-8. PubMed.