THE SHIFT IN THE <EM>APOE4 </EM>RESPONSE: SEX-SPECIFIC OUTCOMES ACROSS ACUTE-TO-CHRONIC<EM> </EM>LPS ADMINISTRATION

Apolipoprotein E genotype (APOE), particularly the APOEε4 allele, is a major genetic risk factor for Alzheimer’s disease, characterized by a hyperresponsive neuroinflammatory profile. Inflammation may play a causal role in accelerating neurodegeneration, which establishes a field that needs better understanding to design prevention strategies for APOEε4 carriers. This study characterizes how neuroinflammation and neurodegeneration are linked to proinflammatory acute or chronic events in APOE4.
ApoE4 homozygous male and female mice were treated with an intraperitoneal dose of 0 or 0,25mg/kg of lipopolysaccharide (LPS) following three temporal lines: acute (single dose), sub-chronic (6 doses in 2 weeks) and chronic (12 doses in 4 weeks). Body weight was monitored, and animals were euthanized 2h after the last LPS injection. Serum and tissues were collected for ELISA and RT-qPCR analysis.
Findings revealed sex-dependent phenotype under LPS challenge and outlined an adaptive tolerance trajectory to LPS. Acute exposure generated robust transcriptional responses affecting neuroinflammation and synaptic markers but were attenuated by the chronic exposure, revealing a shift in the priming response. Males exhibited some alterations in excitatory and inhibitory signalling. Conversely, females presented a pronounced neuroinflammatory response after acute intervention and remained quite elevated after chronic LPS administration.
Our results suggest that peripheral inflammation may alter synaptic functions in apoE4 males, while females are more prone to sustained neuroinflammatory activation. This highlights the APOE4 genotype and the inflammatory course as crucial interacting risk factors in neurodegeneration and the need to address sex-specific therapeutic strategies.