Abstract
Alzheimer’s disease is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Current treatments are unable to achieve satisfactory therapeutic effects or reverse the progression of the disease. Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and neuronal calcineurin may be hyperactivated in AD. To investigate the effects and underlying mechanisms of FK506, a calcineurin inhibitor, on Alzheimer-like behavior and synaptic dysfunction in the 3 × Tg-AD transgenic mouse model of Alzheimer’s disease, we investigated the effect of FK506 on cognitive function and synaptic plasticity in the 3 × Tg-AD transgenic mouse model of Alzheimer’s disease. The results showed that FK506 treatment ameliorated cognitive deficits, as indicated by the decreased latency in the water maze, and attenuated tau hyperphosphorylation in 3 × Tg-AD mice. Treatment with FK506 also reduced the levels of certain markers of postsynaptic deficits, including PSD-95 and NR2B, and reversed the long-term potentiation deficiency and dendritic spine impairments in 3 × Tg-AD mice. These findings suggest that treatment with calcineurin inhibitors such as FK506 can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial Alzheimer’s disease and related tauopathies.
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The authors declare that the data supporting the findings of this study are available within the article and its additional files, or from the authors upon request.
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Acknowledgements
This work was supported by The Foundation of Hubei Science & Technology Department (2022CFB974) to Dong-Sheng Sun.
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This study was initiated and designed by QF; QF directed and coordinated the study; JZ and XFH performed major animal behavior studies, Western blotting, and immunohistochemistry; DSS and JZM performed brain slice electrophysiology recordings, brain Golgi staining, dendritic morphology analysis, and collected and analyzed the data; XYH helped to collect and analyze the data; JZM performed immunohistochemistry, helped to interpret the results, and commented on the manuscript; and QF and JZ wrote the manuscript. All authors read and approved the final manuscript.
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Zeng, J., Hu, XF., Sun, DS. et al. Alzheimer-like behavior and synaptic dysfunction in 3 × Tg-AD mice are reversed with calcineurin inhibition. Exp Brain Res 242, 1507–1515 (2024). https://doi.org/10.1007/s00221-024-06841-8
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DOI: https://doi.org/10.1007/s00221-024-06841-8