Abstract
Acute systemic inflammatory response (SIR) triggers an alteration in the transcription of brain genes related to neuroinflammation, oxidative stress and cells death. These changes are also characteristic for Alzheimer’s disease (AD) neuropathology. Our aim was to evaluate gene expression patterns in the mouse hippocampus (MH) by using microarray technology 12 and 96 h after SIR evoked by lipopolysaccharide (LPS). The results were compared with microarray analysis of human postmortem hippocampal AD tissues. It was found that 12 h after LPS administration the expression of 231 genes in MH was significantly altered (FC > 2.0); however, after 96 h only the S100a8 gene encoding calgranulin A was activated (FC = 2.9). Gene ontology enrichment analysis demonstrated the alteration of gene expression related mostly to the immune-response including the gene Lcn2 for Lipocalin 2 (FC = 237.8), involved in glia neurotoxicity. The expression of genes coding proteins involved in epigenetic regulation, histone deacetylases (Hdac4,5,8,9,11) and bromo- and extraterminal domain protein Brd3 were downregulated; however, Brd2 was found to be upregulated. Remarkably, the significant increase in expression of Lcn2, S100a8, S100a9 and also Saa3 and Ch25h, was found in AD brains suggesting that early changes of immune-response genes evoked by mild SIR could be crucial in AD pathogenesis.
Highlights
The endotoxin hypothesis of neurodegeneration assumes that systemic inflammatory response (SIR) evoked by bacterial endotoxin lipopolysaccharide (LPS) may trigger the cascade of signaling events in the brain leading to dysfunction, degeneration or death of neurons [1]
The results of a mRNA-array based analysis of controls versus Alzheimer’s disease (AD) brains presented in cluster diagram “heat map” format (A) and in bar graph format (B)
Compared to age, gender- and post-mortem interval-matched controls, mRNA for Ch25h, Lipocalin 2 (Lcn2), Saa3, S100 calcium binding protein A8 (S100a8), and S100a9 are significantly up-regulated in AD CA1 to levels 10- to 60fold above controls. * p < 0.05, ** p < 0.01, comparing to control group
Summary
The endotoxin hypothesis of neurodegeneration assumes that systemic inflammatory response (SIR) evoked by bacterial endotoxin lipopolysaccharide (LPS) may trigger the cascade of signaling events in the brain leading to dysfunction, degeneration or death of neurons [1]. Peripheral activation of immune system induces release of pro-inflammatory mediators that coordinate local and systemic response, but they impact the central nervous system (CNS) leading to development of behavioral symptoms defined as “sickness behavior”. In AD, LPS may accumulate in neocortical neurons and impair the efficient readout of neuronal genetic information necessary for the homeostasis and function of brain cells [15]. The endotoxin hypothesis of neurodegeneration proposes that decreasing LPS levels or LPS-induced neuroinflammation may protect the brain against neurodegenerative processes
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