Differential Brain and Cerebrospinal Fluid Proteomic Responses to Acute Prenatal Endotoxin Exposure

Abstract

BackgroundChorioamnionitis (CA) is a risk factor for preterm birth and is associated with neurodevelopmental delay and cognitive disorders. Prenatal in ammation-induced brain injury may resolve during the immediate postnatal period, which is a time of rapid metabolic and brain remodeling. Cerebrospinal uid (CSF) collected at birth may be a critical source of predictive biomarkers. Using pigs as a model of preterm infants exposed to CA, we hypothesized that prenatal lipopolysaccharide (LPS) exposure induces proteome changes in the CSF and brain both at birth and later. MethodsFetal piglets (103 days gestation of the full-term 117 days) were administered intra-amniotic (IA) lipopolysaccharide (LPS) 3 days before preterm delivery by caesarian section. CSF and brain tissue were collected on postnatal Days 1 and 5 (P1 and P5). CSF and hippocampal proteins were pro led by LC-MS-based quantitative proteomics. Neuroin ammatory responses in the cerebral cortex, periventricular white matter and hippocampus were evaluated by immunohistochemistry, and gene expression was evaluated by qPCR. ResultsPigs exposed to LPS in utero showed changes in CSF protein levels at birth but not at P5. Complement protein C3, hemopexin, vasointestinal peptide, carboxypeptidase N subunit 2, ITIH1 and plasminogen expression was upregulated in the CSF, while the expression of proteins associated with axon growth and synaptic functions (FGFR1, BASP1, HSPD1, UBER2N, and RCN2), adhesion (Talin1), and neuronal survival (Atox1) was downregulated. Microglia, but not astrocytes, were activated by LPS at P5 in the hippocampus but not in other brain regions. At this time, marginal increases in complement protein C3, LBP, Hif1a, Basp1, Minpp1 and FGFR1 transcription indicated hippocampal proin ammatory responses. ConclusionA brief period of prenatal endotoxin exposure induces proteome changes in the CSF and brain at birth, but most changes resolve a few days later. The developing hippocampus has high neuronal plasticity in response to perinatal in ammation. Changes in CSF protein expression at birth may help to predict later structural brain damage in preterm infants exposed to variable types and durations of CA-related in ammation in utero.

Analysis of complement system and its related factors in Alzheimer’s disease

“…Among the 23 genes previous studies have shown their correlation with AD, we have: GFAP [ 41 , 42 ], PDGFRβ [ 43 – 45 ], NFKBIA [ 46 ], TNFRSF1B [ 47 ], NOTCH1 [ 48 ], BCL6 [ 49 ], CSF1R [ 50 ], LEP [ 51 ], DCLRE1C [ 52 ], KCNJ10 [ 53 ], MAP2K1 [ 54 ], VIP [ 55 ], SNCA [ 56 ], ENO2 [ 57 ], SST [ 58 ], UCHL1 [ 59 ], HPRT1 [ 60 ], STAT4 [ 61 ], CD14 [ 62 ], ITGB2 [ 63 ], SPP1 [ 64 ], STX1A [ 65 ], and SYP [ 66 ]. And these genes are involved in the regulation of molecules associated with the complement system, for instance, GFAP [ 67 ], PDGFRβ [ 68 ], NFKBIA [ 69 ], TNFRSF1B [ 70 ], NOTCH1 [ 71 ], BCL6 [ 72 ], CSF1R [ 73 ], LEP [ 74 ], DCLRE1C [ 75 ], KCNJ10 [ 76 ], MAP2K1 [ 77 ], VIP [ 78 ], SNCA [ 79 ], ENO2 [ 80 ], SST [ 81 ], UCHL1 [ 82 ], HPRT1 [ 83 ], STAT4 [ 84 ], CD14 [ 85 ], ITGB2 [ 86 ], SPP1 [ 87 ], STX1A [ 88 ], and SYP [ 89 ]. However, few studies have discussed their role in AD pathology by modulating the complement system, our study may be a new perspective for our future exploration of the relationship between AD and the complement system.…”

Proteins Involved in Synaptic Plasticity Are Downregulated in the Cerebrospinal Fluid of Infants With Clinical Sepsis Complicated by Neuroinflammation

“…Besides, decreased levels of EPHA4 may facilitate an anti-inflammatory microglia phenotype, since EphA4 deletion inhibits microglia proliferation and promotes the M2 polarization (Wei et al, 2019 ). Preclinical studies in pigs showed that the microglial response to inflammatory challenges is transient (Muk et al, 2022 ), however the early-life immune activation makes this long-living tissue resident macrophages more sensitive to a secondary inflammatory insult later in life, and may also have long-term behavior impact (Bilbo et al, 2006 ).…”

Porcine Astrocytes and Their Relevance for Translational Neurotrauma Research

“…Recently the Pankratova Lab published a study investigating the exposure of porcine fetuses to intra-amniotic injection of 1 mg liposaccharide (LPS), which can cause intrauterine inflammation at embryonic gestation day 103 (E103) prior to cesarean section delivery at E106 [ 115 ]. They analyzed GFAP immunoreactivity in the cortex, hippocampus, and periventricular white matter at day 1 (P1) and day 5 (P5) after birth.…”