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

ABSTRACT: Female biased pathology and cognitive decline in Alzheimer's disease (AD) have been consistently observed with unclear underlying mechanisms. Although brain sphingolipid ceramide is elevated in AD patients, whether and how ceramide may contribute to sex-specific differences in amyloid pathology is unknown. Here we investigated the sex-specific impact of chronic pharmacological inhibition of neutral sphingomyelinase (nSMase), a key enzyme responsible for ceramide metabolism, on in vivo neuron-derived exosome dynamics, Aβ plaque load, and cognitive function in the APP^NL-F/NL-F knock-in (APP NL-F) AD mouse model. Our results found sex-specific increase of cortical C20:0 ceramide and brain exosome levels only in APP NL-F but not in age-matched WT mice. Although nSMase inhibition sim

SUBMITTER: Mowry FE 

PROVIDER: S-EPMC10777534 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature