Lowering hippocampal miR-29a expression slows cognitive decline and reduces beta-amyloid deposition in 5xFAD mice

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.