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

Authors#

Alessia Sciortino, Thomas Hentrich, Sergio Helgueta Romero, Pierre Garcia, Kristopher Schmit, Melanie Thomas, Rashi Halder, Djalil Coowar, Michel Mittelbronn, Lasse Sinkkonen, Julia Schulze-Hentrich, Manuel Buttini

Abstract#

Cognitive decline is the most common and detrimental, but understudied non-motor symptom of Parkinson’s disease (PD). Neuropathologically, cognitive decline in PD is associated with alpha-synuclein (αSyn) misfolding and synapse loss in hippocampus and prefrontal cortex, leading to cognitive impairment and, ultimately clinically manifest dementia. The molecular underpinnings of PD-associated cognitive decline are unknown. In the present study, longitudinal gene expression profiling was performed to characterise molecular hippocampal alterations in a transgenic mouse overexpressing E46K mutated αSyn, a model of early PD with loss of synaptophysin, a proxy marker of cognition, in hippocampus and cortex. Comparing 4 different ages of mice from both sexes showed that hippocampal gene expression changes were sexually dimorphic and strongly modulated by age and αSyn overexpression. Pathways that emerged across different comparisons were connected to a variety of neuronal functions, collagen synthesis/remodelling, cellular stress, and inflammatory responses. The findings indicate that sex and age are essential covariates to consider when studying PD-associated cognitive decline. The uncovering of early events leading to disease in an animal model is an essential step toward prognostic biomarker identification and early interventions, which may have implications for monitoring, and for timing of therapeutic approaches.