Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of TREM2-mediated microglial activation.

Disrupted lipid homeostasis and neuroinflammation often co-exist in neurodegenerative disorders, including Alzheimer's disease (AD). However, the intrinsic connection and causal relationship between these deficits remain elusive. Our previous studies show that the loss of sulfatide (ST), a class of myelin-enriched lipids, causes AD-like neuroinflammatory responses, cognitive impairment, bladder enlargement, and lipid dyshomeostasis. To better understand the relationship between neuroinflammation and lipid disruption induced by ST deficiency, we established a ST-deficient mouse model with a constitutive Trem2 knockout. Our study demonstrates that TREM2 regulates ST deficiency-induced neuroinflammation and astrocyte activation at the transcriptomic level but does not affect stage 1 disease-associated microglia or astrogliosis at the protein level. Additionally, ST loss-induced lipidome disruption, free water retention, and cognitive impairment persist in the absence of TREM2. Further, these phenotypes are more severe in females compared to males. Collectively, these results emphasize the essential role of TREM2 in mediating lipid loss-associated microglia-mediated neuroinflammation, but not astrogliosis or myelin lipid disruption. Moreover, we demonstrated that attenuating TREM2-mediated neuroinflammation has a limited impact on brain ST loss-induced lipidome alteration or AD-like central and peripheral disorders. Our findings suggest that preserving the lipidome and astrocyte balance may be crucial in decelerating the progression of AD.