Mechanisms of sepsis‐induced inflammation in the aging brain

Abstract

AbstractBackgroundSepsis affects millions worldwide with adults over the age of 65 at particularly high risk. Up to 70% of sepsis patients develop delirium and the severity and length of delirium are strong predictors of acquisition of Alzheimer’s Disease and Related Dementias (AD, ADRD). We hypothesize that older adults and those at risk for AD have augmented neuroinflammation during sepsis that correlates development of delirium and persistence of long‐term cognitive impairment.MethodMale and female wild‐type (young‐3 months and aged‐18 months) and 4 month old Tau P301S transgenic AD mice were used to test the effects of polymicrobial sepsis on markers of neuroimflammation and behavior. Sepsis was induced by intraperitoneal injection of a slurry of cecal contents. Plasma and brain were collected from 8 hours to 7 days post infection for measurement of pro‐inflammatory cytokines (IL‐6, CXCL‐1, TNF‐a) and markers of neuroinflammation (GFAP, IBA1 and s100B) using a combination of protein quantification, multiplex and immunohistochemical approaches. Behavior, including measures of locomotor activity, motor learning (rotarod) and cognition (Y‐maze, nest building) were tested up to 7 days post infection.ResultSepsis increases plasma markers of acute neuroinflammation between 8 and 48 hours that resolves by 7 days. Despite this, mice who have recovered from sepsis have persistent microglial activation in the hippocampus at least 7 days later suggesting prolonged damage. Some recovered mice also have persistent deficits in behavioral tasks including activity and nest building despite appearing healthy and fully recovered. Older WT mice are more susceptible to sepsis as measured by severity of illness (Figure) and mortality and mice genetically predisposed to AD have greater deficits in behavioral measures compared to their WT counterparts following infection.ConclusionSepsis is accompanied acutely by marked neuroinflammation and chronically by microglial activation and behavior deficits. Older age and presence of even early stages of AD‐relevant pathology augment these deficits. Persistent microglial activation may underlie this pathology and prime the aged brain to develop an ADRD‐like syndrome.