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Muscone Ameliorates Synaptic Dysfunction and Cognitive Deficits in APP/PS1 Mice
Yi Liu1,2, Huijie Bian1,2,3, Siyi Xu1,2,4
1Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China.
Background:
Dysfunction of synaptic plasticity leads to memory impairment in Alzheimer's disease (AD). Muscone (Mus) has shown neuroprotective effects in cerebral ischemic models. However, little is known of Mus effects on AD.
Objective:
To investigate the effects of Mus on memory functions and synaptic plasticity in 6-month-old APP/PS1 double-transgenic mice and explore the potential mechanisms.
Methods:
Mus was intraperitoneally injected into APP/PS1 or wild-type mice, and cognitive function was assessed by Novel object recognition and Morris water maze tests. The levels of amyloid-β (Aβ) were evaluated by immunofluorescence staining and ELISA. Synaptic morphology and plasticity were evaluated by Golgi staining and long-term potentiation. Cell viability was examined by Cell Counting Kit-8 assay. The protein levels of histone deacetylase 2 (HDAC2) were accessed by western blotting and Immunofluorescence staining. The protein levels of microtubule associated protein 2 and synaptophysin were analyzed by immunofluorescence staining. The ubiquitination of HDAC2 was examined by co-immunoprecipitation. The interaction of Mus with HDAC2 was predicted by molecular docking analysis.
Results:
Mus treatment attenuated memory dysfunction, reduced Aβ level, and enhanced synaptic plasticity in APP/PS1 mice. In addition, Mus treatment decreased the level of HDAC2 in the hippocampus of APP/PS1 mice and Aβ1-42-induced primary neurons, which might be associated with increased HDAC2 ubiquitination induced by HDAC2 and Mus interaction.
Conclusion:
Mus protected against synaptic plasticity and memory impairment in APP/PS1 mice, and enhanced HDAC2 degradation via ubiquitination, indicating that Mus was a potential drug for AD treatment.
Insights
Muscone improved memory and synaptic plasticity in Alzheimer's disease models by reducing amyloid-beta and enhancing protein degradation. This suggests Muscone is a promising therapeutic candidate for Alzheimer's disease.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Synaptic plasticity dysfunction is a key factor in Alzheimer's disease (AD) related memory impairment.
- Muscone (Mus) demonstrates neuroprotective properties in cerebral ischemia, but its role in AD is largely unexplored.
Purpose of the Study:
- To evaluate the impact of Muscone on memory and synaptic plasticity in a mouse model of Alzheimer's disease (APP/PS1 mice).
- To elucidate the underlying molecular mechanisms of Muscone's effects in AD.
Main Methods:
- Cognitive function was assessed using Novel Object Recognition and Morris Water Maze tests.
- Amyloid-beta (Aβ) levels, synaptic morphology, and plasticity were quantified.
- Histone deacetylase 2 (HDAC2) levels, ubiquitination, and interactions were analyzed using biochemical and computational methods.
Main Results:
- Muscone treatment significantly improved memory deficits and enhanced synaptic plasticity in APP/PS1 mice.
- Muscone reduced amyloid-beta levels and decreased HDAC2 expression in the hippocampus.
- Increased HDAC2 ubiquitination, potentially mediated by Muscone interaction, was observed.
Conclusions:
- Muscone demonstrates therapeutic potential for Alzheimer's disease by mitigating memory impairment and synaptic dysfunction.
- The mechanism involves HDAC2 degradation via ubiquitination, highlighting a novel therapeutic pathway.
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