Long-term blocking of a brain enzyme reduces nerve cell particle spread and lowers Alzheimer's-related protein buildup differently in male and female mice

Chronic inhibition of neutral sphingomyelinase led to a significant reduction in amyloid pathology predominantly in female APP NL-F mice.

• C20:0 ceramide and brain exosome levels increased in female APP NL-F mice compared to age-matched wild-type mice.
• Inhibition of neutral sphingomyelinase blocked exosome spreading in both male and female mice.
• Significantly reduced amyloid pathology was observed mainly in the cortex and hippocampus of female APP NL-F mice.
• A female-specific reduction in spontaneous alternation rate was noted in the T maze test for spatial working memory, which was reversed by chronic nSMase inhibition.
• Changes in ceramide and exosome pathways may contribute to the progression of female-specific amyloid pathology.

Simplified