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MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: Relevance to Alzheimer's disease
Subodh Kumar1, Hallie Morton1, Neha Sawant1
1Internal Medicine Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Background:
MicroRNA-455-3p is one of the highly conserved miRNAs involved in multiple cellular functions in humans and we explored its relevance to learning and memory functions in Alzheimer's disease (AD). Our recent in vitro studies exhibited the protective role of miR-455-3p against AD toxicities in reducing full-length APP and amyloid-β (Aβ) levels, and also in reducing defective mitochondrial biogenesis, impaired mitochondrial dynamics and synaptic deficiencies. In the current study, we sought to determine the function of miR-455-3p in mouse models.
Methods:
For the first time we generated both transgenic (TG) and knockout (KO) mouse models of miR-455-3p. We determined the lifespan extension, cognitive function, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial morphology, dendritic spine density, synapse numbers and synaptic activity in miR-455-3p TG and KO mice.
Results:
MiR-455-3p TG mice lived 5 months longer than wild-type (WT) counterparts, whereas KO mice lived 4 months shorter than WT mice. Morris water maze test showed improved cognitive behavior, spatial learning and memory in miR-455-3p TG mice relative to age-matched WT mice and miR-455-3p KO mice. Further, mitochondrial biogenesis, dynamics and synaptic activities were enhanced in miR-455-3p TG mice, while these were reduced in KO mice. Overall, overexpressed miR-455-3p in mice displayed protective effects, whereas depleted miR-455-3p in mice exhibited deleterious effects in relation to lifespan, cognitive behavior, and mitochondrial and synaptic activities.
Conclusion:
Both mouse models could be ideal research tools to understand the molecular basis of aging and its relevance to AD and other age-related diseases.
Insights
MicroRNA-455-3p enhances lifespan and cognitive function in mice by improving mitochondrial and synaptic activities. Its depletion has detrimental effects, highlighting its role in aging and Alzheimer's disease.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- MicroRNA-455-3p is a conserved miRNA implicated in cellular functions.
- Previous in vitro studies suggested a protective role against Alzheimer's disease (AD) toxicities, including reducing amyloid-beta (Aβ) and improving mitochondrial and synaptic health.
- The in vivo function of miR-455-3p in learning and memory, particularly in the context of AD, remained to be elucidated.
Purpose of the Study:
- To investigate the in vivo function of microRNA-455-3p (miR-455-3p) in learning and memory.
- To determine the impact of miR-455-3p on lifespan, cognitive function, mitochondrial biogenesis, mitochondrial dynamics, and synaptic activity.
- To establish the relevance of miR-455-3p to aging and Alzheimer's disease (AD) through the development of novel mouse models.
Main Methods:
- Generation of transgenic (TG) and knockout (KO) mouse models for miR-455-3p.
- Assessment of lifespan, cognitive function using the Morris water maze test, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial morphology, dendritic spine density, synapse numbers, and synaptic activity in TG and KO mice compared to wild-type (WT) controls.
Main Results:
- miR-455-3p TG mice exhibited a 5-month lifespan extension compared to WT, while KO mice showed a 4-month reduction.
- TG mice demonstrated improved cognitive behavior, spatial learning, and memory, whereas KO mice showed deficits.
- Enhanced mitochondrial biogenesis, dynamics, and synaptic activities were observed in TG mice, with reductions in KO mice, indicating protective effects of overexpression and deleterious effects of depletion.
Conclusions:
- Overexpressed miR-455-3p confers protective effects on lifespan, cognitive function, and mitochondrial and synaptic health in mice.
- Depleted miR-455-3p has deleterious effects on these parameters, underscoring its critical role.
- The generated miR-455-3p TG and KO mouse models serve as valuable tools for studying aging and age-related diseases like AD.
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