Inhibition of serine palmitoyltransferase reduces Aβ and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimer's disease.
Inhibition of serine palmitoyltransferase reduces Aβ and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimer's disease.
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丝氨酸棕榈酰转移酶的抑制可在鼠模型中降低Aβ和TAU高磷酸化：阿尔茨海默氏病的安全治疗策略。
DOI：
10.1016/j.neurobiolaging.2013.02.001
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发表时间：
2013-08
影响因子：
4.2
通讯作者：
Chan C
中科院分区：
文献类型：
--
作者：
Geekiyanage H;Upadhye A;Chan C
常染色体显性突变对家族性阿尔茨海默病（AD）病因学的贡献是很好的特点。然而，导致散发性AD的分子机制尚不清楚。增加的神经酰胺水平在AD患者中是明显的。我们以前报道过，神经酰胺水平的增加，由丝氨酸棕榈酰转移酶（SPT）的增加调节，直接介导淀粉样β（Aβ）的水平。因此，我们通过皮下给予L-环丝氨酸（LCS）抑制AD小鼠模型（TgCRND 8）中的SPT。皮质Aβ42和过度磷酸化的tau蛋白水平随着SPT/神经酰胺的抑制而下调。皮质SPT、神经酰胺和Aβ42水平呈正相关。由于没有观察到明显的毒性作用，抑制SPT可能是改善AD病理的安全治疗策略。我们先前观察到miR-137、-181 c、-9和29 a/B在转录后调节SPT水平，血清中相应的miRNA水平是AD的潜在诊断生物标志物。在这里，我们观察到皮质Aβ42和血清Aβ42之间的负相关性，以及皮质miRNA水平和血清miRNA水平之间的正相关性，这表明它们作为非侵入性诊断生物标志物的潜力。
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 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 β (Aβ) levels. Therefore, we inhibited SPT in an AD mouse model (TgCRND8) through subcutaneous administration of L-cylcoserine (LCS). The cortical Aβ42 and hyperphosphorylated tau levels were down regulated with the inhibition of SPT/ceramide. Positive correlations were observed between cortical SPT, ceramide and Aβ42 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 Aβ42 and sera Aβ42, and a positive correlation between cortical miRNA levels and sera miRNA levels suggesting their potential as non-invasive diagnostic biomarkers.
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DOI：
10.1083/jcb.200207113
发表时间：
2003-01-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ehehalt R;Keller P;Haass C;Thiele C;Simons K
通讯作者：
Simons K
影响因子：
2.3
作者：
Becker, Ivonne;Wang-Eckhardt, Lihua;Eckhardt, Matthias
通讯作者：
Eckhardt, Matthias
影响因子：
4.2
作者：
Gómez-Ramos, A;Díaz-Nido, J;Avila, J
通讯作者：
Avila, J
DOI：
10.1523/jneurosci.3883-11.2011
发表时间：
2011-10-12
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Geekiyanage H;Chan C
通讯作者：
Chan C
影响因子：
4.8
作者：
Chishti, MA;Yang, DS;Westaway, D
通讯作者：
Westaway, D