Sex-specific hippocampal metabolic signatures at the onset of systemic inflammation with lipopolysaccharide in the APPswe/PS1dE9 mouse model of Alzheimer’s disease

Alessandra Agostini,Ding Yuchun,Bai Li,David A Kendall,Marie-Christine Pardon

doi:10.1016/j.bbi.2019.09.019

Abstract

Systemic inflammation enhances the risk and progression of Alzheimer’s disease (AD). Lipopolysaccharide (LPS), a potent pro-inflammatory endotoxin produced by the gut, is found in excess levels in AD where it associates with neurological hallmarks of pathology. Sex differences in susceptibility to inflammation and AD progression have been reported, but how this impacts on LPS responses remains under investigated. We previously reported in an APP/PS1 model of AD that systemic LPS administration rapidly altered hippocampal metabolism in males. Here, we used untargeted metabolomics to comprehensively identify hippocampal metabolic processes occurring at onset of systemic inflammation with LPS (100 µg/kg, i.v.) in APP/PS1 mice, at an early pathological stage, and investigated the sexual dimorphism in this response. Four hours after LPS administration, pathways regulating energy metabolism, immune and oxidative stress responses were simultaneously recruited in the hippocampi of 4.5-month-old mice with a more protective response in females despite their pro-inflammatory and pro-oxidant metabolic signature in the absence of immune stimulation. LPS induced comparable behavioural sickness responses in male and female wild-type and APP/PS1 mice and comparable activation of both the serotonin and nicotinamide pathways of tryptophan metabolism in their hippocampi. Elevations in N-methyl-2-pyridone-5-carboxamide, a major toxic metabolite of nicotinamide, correlated with behavioural sickness regardless of sex, as well as with the LPS-induced hypothermia seen in males. Males also exhibited a pro-inflammatory-like downregulation of pyruvate metabolism, exacerbated in APP/PS1 males, and methionine metabolism whereas females showed a greater cytokine response and anti-inflammatory-like downregulation of hippocampal methylglyoxal and methionine metabolism. Metabolic changes were not associated with morphological markers of immune cell activation suggesting that they constitute an early event in the development of LPS-induced neuroinflammation and AD exacerbation. These data suggest that the female hippocampus is more tolerant to acute systemic inflammation.

Highlights

Alzheimer’s disease (AD), the most common senile dementia, is characterised by a progressive cognitive decline accompanied by the accumulation of aggregated amyloid beta (Aβ) plaques, neurofibrillary tangles made of hyperphosphorylated tau protein, severe brain atrophy and neuroinflammation
Infection-induced systemic inflammation has been proposed as a mechanistic driver of AD pathogenesis (Ashraf et al, 2019; Giridharan et al, 2019), and the presence of acute inflammatory events, such as respiratory infections or delirium have been associated with exacerbations of clinical presentation and precipitous cognitive decline in AD patients (Holmer et al, 2018; Holmes et al, 2009; Ide et al, 2016)
Metabolic data indicated that LPS induced a comparable activation of both the serotonin and nicotinamide pathways of tryptophan metabolism in the hippocampus of WT and APP/PS1 mice of both sexes, with hippocampal levels of the toxic nicotinamide metabolite 2PY being positively associated with the severity of the sickness response

Summary

Introduction

Alzheimer’s disease (AD), the most common senile dementia, is characterised by a progressive cognitive decline accompanied by the accumulation of aggregated amyloid beta (Aβ) plaques, neurofibrillary tangles made of hyperphosphorylated tau protein, severe brain atrophy and neuroinflammation. Infection-induced systemic inflammation has been proposed as a mechanistic driver of AD pathogenesis (Ashraf et al, 2019; Giridharan et al, 2019), and the presence of acute inflammatory events, such as respiratory infections or delirium have been associated with exacerbations of clinical presentation and precipitous cognitive decline in AD patients (Holmer et al, 2018; Holmes et al, 2009; Ide et al, 2016) This suggests that AD patients and people at risk of developing the disease are more susceptible to inflammatory conditions, and that such vulnerability contributes to the development of clinical features of AD. Some sex differences in the association between specific pro-inflammatory mediators and clinical outcomes have been noted (Trollor et al, 2010), but this has not been investigated in detail

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