Dataset Information

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE271598 | GEO | 2025/04/01

REPOSITORIES: GEO

ACCESS DATA

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Project description:Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, how this metabolic interplay may be affected during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in hippocampal brain slices of 5xFAD mice. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, cerebral cortical slices of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. When we explored the brain proteome and metabolome of the 5xFAD mice, we found limited changes, supporting that the functional metabolic disturbances between neurons and astrocytes are early events in AD pathology. In addition, we show that synaptic mitochondrial and glycolytic function was impaired selectively in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex region and cell specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.