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首页> 外文期刊>Molecular and Cellular Biology >Glycogen Synthase Kinase 3 Inhibition Promotes Lysosomal Biogenesis and Autophagic Degradation of the Amyloid-β Precursor Protein
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Glycogen Synthase Kinase 3 Inhibition Promotes Lysosomal Biogenesis and Autophagic Degradation of the Amyloid-β Precursor Protein

机译：糖原合酶激酶3抑制促进溶酶体生物发生和淀粉样β前体蛋白的自噬降解。

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Alzheimer's disease (AD) has been associated with altered activity of glycogen synthase kinase 3 (GSK3) isozymes, which are proposed to contribute to both neurofibrillary tangles and amyloid plaque formation. However, the molecular basis by which GSK3 affects the formation of Aβ remains unknown. Our aim was to identify the underlying mechanisms of GSK3-dependent effects on the processing of amyloid precursor protein (APP). For this purpose, N2a cells stably expressing APP carrying the Swedish mutation were treated with specific GSK3 inhibitors or transfected with GSK3α/β short interfering RNA. We show that inhibition of GSK3 leads to decreased expression of APP by enhancing its degradation via an increase in the number of lysosomes. This induction of the lysosomal/autophagy pathway was associated with nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Our data indicate that GSK3 inhibition reduces Aβ through an increase of the degradation of APP and its carboxy-terminal fragment (CTF) by activation of the lysosomal/autophagy pathway. These results suggest that an increased propensity toward autophagic/lysosomal alterations in AD patients could have consequences for neuronal function.
机译：阿尔茨海默氏病（AD）与糖原合酶激酶3（GSK3）同工酶的活性改变有关，该酶被认为既有助于神经原纤维缠结，又可以促进淀粉样斑块的形成。但是，GSK3影响Aβ形成的分子基础仍然未知。我们的目的是确定淀粉样蛋白前体蛋白（APP）加工中GSK3依赖效应的潜在机制。为此，将稳定表达带有瑞典突变的APP的N2a细胞用特异性GSK3抑制剂处理或转染GSK3α/β短干扰RNA。我们表明抑制GSK3通过增加其溶酶体的数量来增强其降解，从而导致APP表达降低。溶酶体/自噬途径的这种诱导与转录因子EB（TFEB）的核转位有关，TFEB是溶酶体生物发生的主要调控因子。我们的数据表明，GSK3抑制通过溶酶体/自噬途径的激活而增加APP及其羧基末端片段（CTF）的降解，从而降低Aβ。这些结果表明，AD患者自噬/溶酶体改变的倾向增加可能会对神经元功能产生影响。

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