Sex-dependent effect of amyloidosis on functional network ‘hub’ topology is associated with downregulated neuronal gene signatures in the APP swe /PSEN1dE9 double transgenic mouse

Abstract

Background

Extracellular amyloid-β (Aβ) impairs brain-wide functional connectivity, although mechanisms linking Aβ to broader functional network connectivity remain elusive.

Objective

Here, we evaluated the effect of Aβ on fear memory and functional connectome measures in mice.

Methods

Middle-aged (9–11 months of age) double transgenic APP-PS1 mice and age and sex-matched controls were evaluated on a fear conditioning protocol and then imaged at 11.1 Tesla. Brains were harvested and processed for analysis of Aβ plaques and Iba1 immunolabeling in cortex, hippocampus, and basolateral amygdala. Additional RNA sequencing data from separate age, strain, and sex matched mice were analyzed for differentially expressed genes (DEGs) and weighted gene co-expression networks.

Results

In both male and female mice, we observed increased functional connectivity in a dorsal striatal/amygdala network due to Aβ. Increased functional connectivity within this network was matched by increases in AβPP gene expression, Aβ and Iba1 immunolabeling, and an upregulated cluster of DEGs involved in the immune response. Conversely, the network measure representing node ‘hubness’, eigenvector centrality, was increased in prefrontal cortical brain regions, but only in female APP-PS1 mice. This female specific-effect of amyloid was associated with downregulation of a cluster of DEGs involved in cortical and striatal GABA transmission, anxiogenic responses, and motor activity, in female APP-PS1 mice, but not males.

Conclusions

Our results contribute to a growing literature linking between Aβ, immune activation and functional network connectivity. Furthermore, they reveal effects of Aβ on gene expression patterns in female mice that may contribute to amyloidosis-induced dysregulation of non-cognitive circuitry.