Antisense oligonucleotide (ASO) therapy for neurological disease has been successful in clinical settings and its potential has generated hope for Alzheimer’s disease (AD). We previously described that ablating SNCA encoding for α-synuclein (αSyn) in a mouse model of AD was beneficial. Here, we sought to demonstrate whether transient reduction of αSyn expression using ASOSNCA could be therapeutic in a mouse model of AD. The efficacy of the ASOSNCA was measured via immunocytochemistry, RT-qPCR and western blotting. To assess spatial learning and memory, ASOSNCA or PBS-injected APP and non-transgenic (NTG) mice, and separate groups of SNCA-null mice, were tested on the Barnes circular maze. Hippocampal slice electrophysiology and transcriptomic profiling were used to explore synaptic function and differential gene expression between groups. Reduction of SNCA transcripts alleviated cognitive deficits in male transgenic animals, but surprisingly, not in females. To determine the functional cause of this differential effect, we assessed memory function in SNCA-null mice. Learning and memory were intact in male mice but impaired in female animals, revealing that the role of αSyn on cognitive function is sex-specific. Transcriptional analyses identified a differentially expressed gene network centered around EGR1, a central modulator of learning and memory, in the hippocampi of SNCA-null mice. Thus, these novel results demonstrate that the function of αSyn on memory differs between male and female brains.
Bibliographical noteFunding Information:
We thank the University of Minnesota Genomics Center for their support and Dr. Ying Zhang for technical consultation.
This work was supported by grants from the National Institutes of Health (NIH) to SEL (RF1-AG044342, RF1-AG070296, R21-AG065693, R01-AG077743, R01-NS092918, R01-AG062135 and R56-NS113549), to MKL (AG062135, NS108686, NS086074, NS092093). Training grant support for graduate students (T32-NS105604). This study was supported by a grant from the Winston and Maxine Wallin Neuroscience Discovery Fund. Additional support included start-up funds from the University of Minnesota Foundation and bridge funds from the Institute of Translational Neuroscience to SEL.
© 2022, The Author(s).
- Alzheimer’s disease
- Antisense oligonucleotide
- Early growth response 1
- Spatial memory
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural