Sex-dependent effects of amyloidosis on functional network hub topology is associated with downregulated neuronal gene signatures in the APPswe/PSEN1dE9 double transgenic mouse

BackgroundExtracellular amyloid-{beta} (A{beta}) impairs brain-wide functional connectivity, although mechanisms linking A{beta} to broader functional network connectivity remain elusive. ObjectiveHere, we evaluated the effect of A{beta} on fear memory and functional connectome measures in mice. MethodsMiddle-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 A{beta} 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. ResultsIn both male and female mice, we observed increased functional connectivity in a dorsal striatal/amygdala network due to A{beta}. Increased functional connectivity within this network was matched by increases in A{beta}PP gene expression, A{beta} 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. ConclusionsOur results contribute to a growing literature linking between A{beta}, immune activation and functional network connectivity. Furthermore, they reveal effects of A{beta} on gene expression patterns in female mice that may contribute to amyloidosis-induced dysregulation of non-cognitive circuitry.