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. 2024 Jul 18;45(4):857-874.
doi: 10.24272/j.issn.2095-8137.2024.085.

NLRP3-mediated autophagy dysfunction links gut microbiota dysbiosis to tau pathology in chronic sleep deprivation

Na Zhao  1 , Xiu Chen  1 , Qiu-Gu Chen  1 , Xue-Ting Liu  1 , Fan Geng  1 , Meng-Meng Zhu  1 , Fu-Ling Yan  1 , Zhi-Jun Zhang  1 , Qing-Guo Ren  1   2
Affiliations

NLRP3-mediated autophagy dysfunction links gut microbiota dysbiosis to tau pathology in chronic sleep deprivation

Na Zhao et al. Zool Res. .

Abstract
in English, Chinese

Emerging evidence indicates that sleep deprivation (SD) can lead to Alzheimer's disease (AD)-related pathological changes and cognitive decline. However, the underlying mechanisms remain obscure. In the present study, we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD. Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis, elevated NLRP3 inflammasome expression, GSK-3β activation, autophagy dysfunction, and tau hyperphosphorylation in the hippocampus. Colonization with the "SD microbiota" replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice. Remarkably, both the deletion of NLRP3 in NLRP3 -/- mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux, suppressed tau hyperphosphorylation, and ameliorated cognitive deficits induced by chronic SD, while GSK-3β activity was not regulated by the NLRP3 inflammasome in chronic SD. Notably, deletion of NLRP3 reversed NLRP3 inflammasome activation, autophagy deficits, and tau hyperphosphorylation induced by GSK-3β activation in primary hippocampal neurons, suggesting that GSK-3β, as a regulator of NLRP3-mediated autophagy dysfunction, plays a significant role in promoting tau hyperphosphorylation. Thus, gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction, ultimately leading to cognitive deficits. Overall, these findings highlight GSK-3β as a regulator of NLRP3-mediated autophagy dysfunction, playing a critical role in promoting tau hyperphosphorylation.

越来越多的证据表明，睡眠剥夺(SD)可以导致阿尔茨海默病(AD)相关的病理改变和认知功能下降。然而，潜在的机制尚不清楚。在该研究中，我们证明了微生物-肠-脑轴在慢性SD所致的认知障碍中发挥重要作用，并在慢性SD模型中揭示了肠道微生物影响认知功能的潜在途径。我们发现，除认知功能下降外，慢性睡眠剥夺小鼠的肠道菌群发生紊乱，海马中NLRP3炎症小体激活、GSK-3β激活、自噬功能障碍以及tau蛋白过度磷酸化。“SD微生物群”的定植几乎模拟了慢性睡眠剥夺小鼠中观察到的病理学和行为学异常。值得注意的是，无论是使用 NLRP3 -/- 小鼠中还是在海马中特异性敲除NLRP3都恢复了自噬通路，抑制了tau蛋白的过度磷酸化，并改善了慢性SD引起的认知缺陷，而在慢性SD中，GSK-3β活性不受NLRP3炎症小体的调节。接下来我们在原代海马神经元中发现，GSK-3β激活引起了NLRP3炎症小体激活、自噬缺陷和tau蛋白过度磷酸化，但是NLRP3的缺失逆转了自噬缺陷和tau蛋白过度磷酸化，这表明GSK-3β作为tau激酶和NLRP3的调节因子介导自噬功能障碍，共同促进tau蛋白过度磷酸化，尽管GSK-3β仍然被激活，但NLRP3缺陷导致的自噬功能恢复足以抑制tau蛋白的过度磷酸化，因此，GSK-3β作为NLRP3的调节因子介导的自噬功能障碍，在促进tau蛋白过度磷酸化和聚集方面发挥着更显著的作用。综上，这些发现表明，肠道菌群失调是慢性SD的一个始动因素，通过NLRP3介导的自噬功能障碍驱动tau蛋白病理，并最终导致认知缺陷。此外，GSK-3β作为NLRP3的调节因子介导的自噬功能障碍，在促进tau蛋白过度磷酸化中发挥着更重要的作用。.

Keywords: Autophagy; Chronic sleep deprivation; GSK-3β; Microbiota-gut-brain axis; NLRP3 inflammasome; Tau pathology.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Chronic SD induced cognitive deficits in mice
Figure 2
Figure 2
Chronic SD induced tau hyperphosphorylation and GSK-3β activation in the hippocampus of mice
Figure 3
Figure 3
Chronic SD induced NLRP3 inflammasome activation and autophagy inhibition in the hippocampus of mice
Figure 4
Figure 4
SD microbiota transplantation impaired cognitive function, increased tau phosphorylation, and activated GSK-3β
Figure 5
Figure 5
SD microbiota transplantation inhibited autophagic flux and enhanced NLRP3 inflammasome activity
Figure 6
Figure 6
Behavioral and pathological changes induced by chronic SD were reversed in NLRP3-/- mice
Figure 6
Figure 6
Figure 7
Figure 7
Knockdown of NLRP3 in the hippocampus restored autophagic flux, suppressed tau hyperphosphorylation, and ameliorated cognitive deficits
Figure 8
Figure 8
Deletion of NLRP3 reversed NLRP3 inflammasome activation, autophagy deficits, and tau hyperphosphorylation caused by Akt inhibitor-induced activation of GSK-3β in primary hippocampal neurons
See this image and copyright information in PMC

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