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Lowering hippocampal miR-29a expression slows cognitive decline and reduces beta-amyloid deposition in 5xFAD mice
Zhen Mei1, Jiaqi Liu1, Jason P Schroeder1
1Emory University.
Abstract:
microRNA-29a (miR-29a) increases with age in humans and mice, and, in the brain, it has a role in neuronal maturation and response to inflammation. We previously associated higher miR-29a levels in human brain with faster antemortem cognitive decline, suggesting that lowering miR-29a levels could ameliorate memory impairment in the 5xFAD AD mouse model. To test this hypothesis, we generated an adeno-associated virus (AAV) expressing GFP and a miR-29a "sponge" or empty vector. We found that the AAV expressing miR-29a sponge functionally reduced miR-29a levels, and improved measures of memory in the Morris water maze and fear condition paradigms when sponge delivered to hippocampi of 5XFAD and WT mice. miR-29a sponge expression significantly reduced hippocampal beta-amyloid deposition in 5XFAD mice and lowered astrocyte and microglia activation in both 5XFAD and WT mice. Using transcriptomic and proteomic sequencing, we identified Plxna1 and Wdfy1 as putative effectors at the transcript and protein level in WT and 5XFAD mice, respectively. These data indicate that miR-29a promotes AD-like neuropathology and negatively regulates cognition, making it and its target genes attractive therapeutic targets for the treatment of neurodegenerative disease.
Insights
microRNA-29a (miR-29a) reduction improved memory and reduced Alzheimer's disease pathology in mice. Lowering miR-29a offers a potential therapeutic strategy for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- microRNA-29a (miR-29a) levels increase with age and influence brain functions like neuronal maturation and inflammation response.
- Higher miR-29a in human brains correlates with accelerated cognitive decline, suggesting a role in Alzheimer's disease (AD).
Approach:
- Adeno-associated virus (AAV) vectors expressing a miR-29a sponge were used to functionally reduce miR-29a levels in 5xFAD AD mouse models and wild-type (WT) mice.
- Behavioral tests (Morris water maze, fear conditioning) assessed memory function, while molecular analyses examined beta-amyloid deposition and neuroinflammation (astrocyte and microglia activation).
- Transcriptomic and proteomic analyses identified potential downstream targets of miR-29a, including Plxna1 and Wdfy1.
Key Points:
- Adeno-associated virus-mediated delivery of a miR-29a sponge effectively lowered miR-29a levels in the hippocampus.
- Reduced miR-29a levels significantly improved memory performance in both 5xFAD and WT mice.
- miR-29a inhibition decreased beta-amyloid plaque load and attenuated neuroinflammation in the 5xFAD model.
Conclusions:
- microRNA-29a actively promotes Alzheimer's disease-like neuropathology and impairs cognitive function.
- Targeting miR-29a and its downstream effectors represents a promising therapeutic avenue for neurodegenerative diseases.
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