Knockdown of microglial iron import gene, DMT1, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer's disease.

Background: Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer's disease (AD). , microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name ) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease . These studies determined the effects of microglial-specific knockdown of on AD-related cognitive decline and microglial transcriptional phenotype.

Methods: experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial knockdown on AD-related phenotypes , triple-transgenic ; ; mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b + microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted.

Results: DMT1 inhibition robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. , female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and mice. Hippocampal microglia from females displayed significant increases in , , and the iron-export gene, , compared to control cells. cells from females also exhibited decreased expression of markers associated with disease-associated microglia (DAMs), such as , , and .

Conclusions: This work suggests a sex-specific role for microglial iron import gene in propagating behavioral and cognitive phenotypes in the model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.