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Lowering Hippocampal miR-29a Expression Slows Cognitive Decline and Reduces Beta-Amyloid Deposition in 5×FAD Mice
Zhen Mei1,2, Jiaqi Liu1, Jason P Schroeder3
1Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
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 found higher miR-29a levels in the human brain to be associated with faster antemortem cognitive decline, suggesting that lowering miR-29a levels could ameliorate memory impairment in the 5×FAD AD mouse model. To test this, 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 delivered to the hippocampi of 5×FAD and WT mice. miR-29a sponge significantly reduced hippocampal beta-amyloid deposition in 5×FAD mice and lowered astrocyte and microglia activation in both 5×FAD 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 5×FAD mice, respectively. These data indicate that lower miR-29a levels mitigate cognitive decline, making miR-29a and its target genes worth further evaluation as targets to mitigate Alzheimer's disease (AD).
Insights
Lowering microRNA-29a (miR-29a) levels improved memory and reduced Alzheimer's disease pathology in mice. This suggests miR-29a is a potential therapeutic target for cognitive decline.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- microRNA-29a (miR-29a) levels increase with age and influence brain function.
- Higher miR-29a correlates with faster cognitive decline in humans.
- miR-29a's role in Alzheimer's disease (AD) pathology is under investigation.
Purpose of the Study:
- To investigate if reducing miR-29a levels can ameliorate memory impairment and AD pathology in a mouse model.
- To identify potential molecular targets of miR-29a in the brain.
Main Methods:
- Adeno-associated virus (AAV) delivery of a miR-29a sponge or empty vector to the hippocampus of 5×FAD (AD model) and wild-type (WT) mice.
- Behavioral testing using Morris water maze and fear conditioning.
- Analysis of hippocampal beta-amyloid deposition, glial activation (astrocytes and microglia), and gene/protein expression (transcriptomics and proteomics).
Main Results:
- AAV-mediated miR-29a sponge successfully reduced miR-29a levels.
- miR-29a sponge delivery improved memory performance in both 5×FAD and WT mice.
- Reduced beta-amyloid deposition and glial activation were observed in 5×FAD mice treated with the miR-29a sponge.
- Plxna1 and Wdfy1 were identified as potential downstream targets of miR-29a.
Conclusions:
- Lowering miR-29a levels mitigates cognitive deficits and key Alzheimer's disease pathologies in mice.
- miR-29a and its identified target genes (Plxna1, Wdfy1) represent promising therapeutic targets for AD.
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