Proteostasis mechanisms mediated by macroautophagy/autophagy are altered in neurodegenerative diseases such as Alzheimer disease (AD) and their recovery/enhancement has been proposed as a therapeutic approach. From the two central nodes in the anabolism–catabolism balance, it is generally accepted that mechanistic target of rapamycin kinase complex 1 (MTORC1)_ activation leads to the inhibition of autophagy, whereas adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) has the opposite role. In AD, amyloid beta (Aβ) production disturbs the optimal neuronal/glial proteostasis. As astrocytes are essential for brain homeostasis, the purpose of this work was to analyze if the upregulation of autophagy in this cell type, either by MTORC1 inhibition or AMPK activation, could modulate the generation/degradation of β-amyloid. By using primary astrocytes from amyloid beta precursor protein (APP)/Presenilin 1 (PSEN1) mouse model of AD, we confirmed that MTORC1 inhibition reduced Aβ secretion through moderate autophagy induction. Surprisingly, pharmacologically increased activity of AMPK did not enhance autophagy but had different effects on Aβ secretion. Conversely, AMPK inhibition did not affect autophagy but reduced Aβ secretion. These puzzling data were confirmed through the overexpression of different mutant AMPK isoforms: while only the constitutively active AMPK increased autophagy, all versions augmented Aβ secretion. We conclude that AMPK has a significantly different role in primary astrocytes than in other reported cells, similar to our previous findings in neurons. Our data support that perhaps only a basal AMPK activity is needed to maintain autophagy whereas the increased activity, either physiologically or pharmacologically, has no direct effect on autophagy-dependent amyloidosis. These results shed light on the controversy about the therapeutic effect of AMPK activation on autophagy induction.

中文翻译：

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APP/PSEN1 星形胶质细胞中 MTORC1 抑制增强了自噬介导的 β-淀粉样蛋白清除，但 AMPK 激活没有增强

由巨自噬/自噬介导的蛋白质稳态机制在阿尔茨海默病（AD）等神经退行性疾病中发生改变，并且它们的恢复/增强已被提议作为一种治疗方法。从合成代谢-分解代谢平衡的两个中心节点来看，人们普遍认为雷帕霉素激酶复合物 1 (MTORC1)_ 激活的机制靶标会导致自噬的抑制，而腺苷 5'-单磷酸 (AMP) 激活的蛋白激酶 ( AMPK) 具有相反的作用。在 AD 中，β 淀粉样蛋白 (Aβ) 的产生会扰乱最佳的神经元/神经胶质蛋白稳态。由于星形胶质细胞对于大脑稳态至关重要，因此这项工作的目的是分析这种细胞类型中自噬的上调（通过 MTORC1 抑制或 AMPK 激活）是否可以调节 β-淀粉样蛋白的生成/降解。通过使用来自 AD 淀粉样蛋白 β 前体蛋白 (APP)/早老素 1 (PSEN1) 小鼠模型的原代星形胶质细胞，我们证实 MTORC1 抑制通过适度的自噬诱导减少 Aβ 分泌。令人惊讶的是，药理学上增加 AMPK 活性并没有增强自噬，但对 Aβ 分泌有不同的影响。相反，AMPK 抑制不会影响自噬，但会减少 Aβ 分泌。这些令人费解的数据通过不同突变 AMPK 同工型的过度表达得到了证实：虽然只有组成型活性 AMPK 增加了自噬，但所有版本都增加了 Aβ 分泌。我们得出的结论是，AMPK 在原代星形胶质细胞中的作用与在其他报道的细胞中的作用显着不同，这与我们之前在神经元中的发现相似。我们的数据支持，也许只需要基础 AMPK 活性来维持自噬，而增加的活性，无论是生理上还是药理学上，对自噬依赖性淀粉样变性没有直接影响。这些结果揭示了有关 AMPK 激活对自噬诱导的治疗效果的争议。