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

Jul 15, 2024Zoological research

Autophagy problems caused by NLRP3 connect gut bacteria imbalance to tau buildup in long-term sleep loss

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Abstract

Chronic sleep deprivation in mice led to cognitive decline and gut microbiota dysbiosis.

Chronic sleep deprivation is associated with elevated NLRP3 inflammasome expression and GSK-3β activation.
Autophagy dysfunction and tau hyperphosphorylation were observed in the hippocampus of sleep-deprived mice.
Colonization with 'SD microbiota' replicated cognitive and pathological changes seen in chronic sleep-deprived mice.
Deleting NLRP3 in mice restored autophagic function and reduced tau hyperphosphorylation, improving cognitive deficits.
GSK-3β activity is not regulated by the NLRP3 inflammasome during chronic sleep deprivation.
Gut microbiota dysbiosis may contribute to tau pathology through NLRP3-mediated autophagy dysfunction.

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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 inmice 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. NLRP3 -/-

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

Abstract

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