Temporal impact of sepsis on Alzheimer's disease pathology and neuroinflammation

Epidemiological evidence has reported an associative link between sepsis survivorship and increased risk of dementia, particularly Alzheimer's disease (AD). Paradoxically, population studies show females are less susceptible to sepsis but more vulnerable to post-sepsis dementia, including Alzheimer's disease (AD). Here, we examined the temporal impacts of sepsis on AD pathology using an AD-model (TgCRND8) and wild-type mice, assessing outcomes at 7 days and 3 months post-sepsis. Following 7-days recovery, all male and female post-septic mice showed robust systemic immune activation. At this time, the female AD-model mice accumulated higher hippocampal amyloid-beta (Aβ) and upregulated AD-type transcriptomic signature. On the other hand, male AD-model mice showed no Aβ changes. Notably, wild-type post-septic males, but not females, displayed robust astrocytosis, with little change in microglial proliferation. By 3 months post-sepsis, microgliosis was specifically elevated in wild-type females, indicating a prolonged central immune response. At this time, both male and female AD-model mice showed exacerbated Aβ and anxiety. Gene network analysis revealed a stronger female immune response, while the male response was linked to estrogen receptor (ESR) signaling, with increased ERα protein observed in the brains of post-septic AD males. Together, our data highlights a sex-dimorphic temporal response in post-sepsis neuroinflammation, with ESR signaling playing a key role in males, while Aβ burden is affected similarly in both males and females.