Metabolic syndrome in New Zealand Obese mice promotes microglial-vascular interactions and reduces microglial plasticity

Metabolic syndrome (MetS) puts patients more at risk for neurodegenerative diseases such as Alzheimers disease (AD). Microglia are implicated as causal factors in AD, however, the effect of MetS on microglia has not been characterized. To address this, we contrasted New Zealand Obese (NZO) with C57BL/6J (B6J) mice in combination with a high fat/high sugar diet (HFD). Irrespective of diet, NZO mice displayed a broader array of MetS-relevant phenotypes compared to B6J mice fed a HFD. Single cell RNA-sequencing of microglia predicted transcriptional shifts indicative of reduced responsiveness and increased vascular interactions in NZO, but not B6J HFD mice. Significant cerebrovascular fibrin deposition and increased perivascular accumulation of microglia were observed in NZO relative to B6J HFD mice. Further, compared to the widely used B6J.APP/PS1 mice, NZO.APP/PS1 exhibited increased amyloid plaque sizes alongside an increase in microhemorrhages. Overall, our work supports a model whereby MetS alters microglia-vascular interactions, compromising microglial plasticity. ### Competing Interest Statement The authors have declared no competing interest.