Age-related differences in secondary neuroinflammation and amyloid-β deposition in a rat sepsis model

Objectives For unknown reasons, cortical binding of amyloid-beta (Aβ) PET agents can be seen in many patients without Alzeimer's disease. Aβ may both prevent inflammation-induced oxidative injury in the brain and potentiate a cerebral inflammatory cycle. Systemic inflammatory conditions may result in neuroinflammation. Sepsis may cause short and long term cognitive deficit, but it is unknown whether this results in increased Aβ plaque deposition in the brain or whether age-specific vulnerabilities may exist. The objective was to determine whether young and old rats differ in sepsis-induced neuroinflammation and Aβ plaque deposition.

Methods Young (2-4 month) and aged (17-20 month) male Sprague Dawley rats were injected IP with 10 mg/kg E.Coli lipopolysaccharide (LPS). Control and LPS-induced serum and brain levels of inflammatory cytokines TNF-α, IL-6, and IL-1β were measured by ELISA at 1 d, 3 d, and 7-9 d post LPS administration. Soluble Aβ was compared by Western Blot analysis of brain homogenates. Aβ plaque burden in the brain was compared by immunostaining of brain sections.

Results In response to experimental sepsis, young rats (but not old) show a transient early increase in serum IL1-β. There was an increase in IL-1β in the brain of young (8-fold) and old (5.2-fold) rats at 1d post LPS, which co-localized with activated microglia, thereafter clearing. Minimal increases in TNFα and IL6 occurred in the brain following LPS. There was a 2-fold increase in soluble Aβ in brains of all rats 1d after LPS, thereafter progressively clearing. The old control rats showed a 2-fold greater Aβ plaque content in the brain than young controls. Sepsis resulted in a > 3-fold Aβ plaque increase in young rats (exceeding old rat control levels), and a 2-fold increase in old rats, which did not clear with time.

Conclusions Inflammatory stimuli, such as sepsis causes secondary neuroinflammation and Aβ plaque deposition in the brain. Young rats show a heightened sensitivity to this process than do old rats. The neurocognitive and long term consequences of this process are still unknown.