Chronic nSMase inhibition suppresses neuronal exosome spreading and sex-specifically attenuates amyloid pathology in APP knock-in Alzheimer's disease mice

Jun 26, 2023Neurobiology of disease

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

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Abstract

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.

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