Inhibition of serine palmitoyltransferase reduces Aβ and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimer's disease

NEUROBIOLOGY OF AGING

卷:34

Article

Geekiyanage, Hirosha¹  Upadhye, Aditi²  Chan, Christina^1,3,4 

[1] Michigan State Univ, Genet Program, E Lansing, MI 48824 USA

[2] Michigan State Univ, Lyman Briggs Program, E Lansing, MI 48824 USA

[3] Michigan State Univ, Dept Chem Engn & Mat Sci, E Lansing, MI 48824 USA

[4] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA

关键词: Alzheimer's disease;    Serine palmitoyltransferase;    Inhibition;    Amyloid beta;    Tau hyperphosphorylation;    MicroRNA;   

DOI  :  10.1016/j.neurobiolaging.2013.02.001

来源: Elsevier

【 摘 要 】

The contribution of the autosomal dominant mutations to the etiology of familial Alzheimer's disease (AD) is well characterized. However, the molecular mechanisms contributing to sporadic AD are less well understood. Increased ceramide levels have been evident in AD patients. We previously reported that increased ceramide levels, regulated by increased serine palmitoyltransferase (SPT), directly mediate amyloid beta (A beta) levels. Therefore, we inhibited SPT in an AD mouse model (TgCRND8) through subcutaneous administration of L-cylcoserine. The cortical A beta(42) and hyperphosphorylated tau levels were down-regulated with the inhibition of SPT/ceramide. Positive correlations were observed among cortical SPT, ceramide, and A beta(42) levels. With no evident toxic effects observed, inhibition of SPT could be a safe therapeutic strategy to ameliorate the AD pathology. We previously observed that miR-137, -181c, -9, and 29a/b post-transcriptionally regulate SPT levels, and the corresponding miRNA levels in the blood sera are potential diagnostic biomarkers for AD. Here, we observe a negative correlation between cortical A beta(42) and sera A beta(42), and a positive correlation between cortical miRNA levels and sera miRNA levels suggesting their potential as noninvasive diagnostic biomarkers. (c) 2013 Elsevier Inc. All rights reserved.

【 授权许可】

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