Leptin regulates amyloid β production via the γ-secretase complex

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Niedowicz, Dana M.^1,2  Studzinski, Christa M.¹  Weidner, Adam M.^1,2  Platt, Thomas L.^1,2  Kingry, Kristen N.²  Beckett, Tina L.^1,2  Bruce-Keller, Annadora J.³  Keller, Jeffrey N.³  Murphy, M. Paul^1,2 

[1] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA

[2] Univ Kentucky, Dept Cellular & Mol Biochem, Lexington, KY 40506 USA

[3] Louisiana State Univ, Pennington Biomed Res Ctr, Inst Dementia Res & Prevent, Baton Rouge, LA 70808 USA

关键词: Leptin;    Presenilin;    gamma-secretase;    beta-amyloid;    Alzheimer's disease;   

DOI  :  10.1016/j.bbadis.2012.12.009

来源: Elsevier

【 摘 要 】

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, affecting an estimated 5.3 million people in the United States. While many factors likely contribute to AD progression, it is widely accepted that AD is driven by the accumulation of beta-amyloid (A beta), a small, fibrillogenic peptide generated by the sequential proteolysis of the arnyloid precursor protein by the beta- and gamma-secretases. Though the underlying causes of A beta accumulation in sporadic AD are myriad, it is clear that lifestyle and overall health play a significant role. The adipocyte-derived hormone leptin has varied systemic affects, including neuropeptide release and neuroprotection. A recent study by Lieb et al. (2009) showed that individuals with low plasma leptin levels are at greater risk of developing AD, through unknown mechanisms. In this report, we show that plasma leptin is a strong negative predictor of A beta levels in the mouse brain, supporting a protective role for the hormone in AD onset. We also show that the inhibition of A beta accumulation is due to the downregulation of transcription of the gamma-secretase components. On the other hand, beta-secretase expression is either unchanged (BACE1) or increased (BACE2). Finally, we show that only presenilin I (PSI) is negatively correlated with plasma leptin at the protein level (p<0.0001). These data are intriguing and may highlight a role for leptin in regulating the onset of amyloid pathology and AD. (C) 2013 Elsevier B.V. All rights reserved.

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