Core circadian clock gene expression is consistently downregulated in Alzheimer's disease (AD) across four human brain datasets.
Knockdown of the circadian clock gene in the hippocampus of mice resulted in dysbiosis of gut microbiota and cognitive dysfunction.
Impairment of the intestinal barrier and activation of neuroinflammatory signaling were observed in mice with hippocampal knockdown.
Disturbances in intestinal sphingolipid metabolism pathways were linked to activation of the in the brain.
Fecal microbiota transplantation mimicked the cognitive and pathological changes associated with hippocampal deficiency.
Administration of the S1P receptor agonist FTY720 improved cognitive function and reduced neuroinflammation in mice.
Simplified
BACKGROUND: Alzheimer's disease (AD) is characterized by extracellular Aβ deposition and tau hyperphosphorylation, leading to synaptic dysfunction and cognitive decline. Mounting evidence indicates that circadian rhythm disorders are associated with increased AD risks. Growing evidence implicates the microbiota-gut-brain axis and its metabolites as critical modulators of both circadian physiology and AD pathology. However, the molecular mechanism through which circadian disturbance modulates gut-brain communication to influence AD pathogenesis remains poorly understood.
METHODS: Core circadian clock gene expression was assessed across four AD human brain datasets, and foundto be the only gene consistently downregulated. To investigate its functional role in vivo, we established a mouse model with hippocampal-specificknockdown. Cognitive performance, gut microbiota composition, and metabolic alterations were evaluated using the Morris water maze, 16 S rRNA sequencing, and untargeted metabolomics, respectively. Intestinal barrier integrity, blood-brain barrier function, and neuroinflammatory signaling were examined through immunohistochemistry, immunofluorescence, and Western blotting. The contribution of microbiota disturbance was tested using fecal microbiota transplantation (FMT). The involvement of sphingolipid signaling was further assessed through FMT, pharmacological modulation with the S1PR agonist FTY720, NLRP3 knockout mice, and microglial assays. Cry2Cry2
RESULTS: We found that the expression ofconsistently decreased in the AD group in four AD-related datasets. Then, knockdown ofin the hippocampus () caused dysbiosis of gut microbiota, intestinal barrier impairment, cognitive dysfunction and tau pathology in mice. Intriguingly, along with the disturbance in intestinal sphingolipid metabolism pathways, activation of the was found in the brain ofmice. Transplantation of "microbiota" mimicked the pathological and behavioral changes induced by hippocampaldeficiency. Administration of S1PR agonist FTY720 significantly improved cognitive impairment and decreased the expression of NLRP3 inmice, and knockdown ofin NLRP3mice alleviated tau pathology and cognitive impairment. FTY720 and S1PR1 antagonist W146 dose-dependently modulated the expression of NLRP3 in BV2 cells. Overexpressingin the hippocampus significantly alleviated the tau pathology and cognitive decline in APP/PS1 mice. Cry2Cry2shCry2shCry2shCry2Cry2shCry2Cry2Cry2 −/−
CONCLUSION: Hippocampaldeficiency leads to cognitive impairment through the gut-brain axis mediated S1P/NLRP3/IL-1β pathway and might provide a potential therapeutic target for AD.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03706-5.
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Declarations. Ethics approval and consent to participate: All animal-related procedures were performed in accordance with ethical standards and were approved by the Institutional Animal Care and Use Committee of Southeast University (20210924075). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
