Transcriptional Dysregulation in the Hippocampus of a Mouse Model for Parkinson's - Linked Cognitive Decline is Driven by Sex, Age, and Alpha-synuclein overexpression

Cognitive decline is the most common and detrimental non-motor symptom of Parkinson’s disease (PD), and is an understudied disease entity. Pathologically, cognitive decline in PD is associated with alpha-synuclein (aSyn) misfolding and synapse loss in hippocampus and prefrontal cortex, leading to cognitive impairment and, ultimately, dementia. The mechanisms of cognitive decline and the factors driving them in PD are unknown. In the present study, we have used longitudinal gene expression profiling to characterise hippocampal molecular events in a transgenic mouse overexpressing E46K mutated aSyn, a model of early PD. Uncovering early events leading to disease is an essential step toward prognostic biomarker identification and early interventions. Transgenic aSyn induced synaptophysin loss in hippocampus and cortex of these mice. Comparing 4 different ages of mice from both sexes uncovered that hippocampal gene expression changes are sexually dimorphic and strongly modulated by the age, and by aSyn overexpression. Pathways that emerged across different comparisons were connected to a variety of neuronal functions, collagen synthesis/remodeling, cellular stress, and inflammatory responses. The findings indicate that sex and age are essential factors to consider when studying PD-associated cognitive decline. This may have important implications for prognostic biomarker identification and monitoring, and for timing of therapeutic approaches.