Abstract
Several independent laboratories have recently reported the detection of bacterial nucleic acid sequences or bacterial-derived neurotoxins, such as highly inflammatory lipopolysaccharide (LPS), within Alzheimer’s disease (AD) affected brain tissues. Whether these bacterial neurotoxins originate from the gastrointestinal (GI) tract microbiome, a possible brain microbiome or some dormant pathological microbiome is currently not well understood. Previous studies indicate that the co-localization of pro-inflammatory LPS with AD-affected brain cell nuclei suggests that there may be a contribution of this neurotoxin to genotoxic events that support inflammatory neurodegeneration and failure in homeostatic gene expression. In this report we provide evidence that in sporadic AD, LPS progressively accumulates in neuronal parenchyma and appears to preferentially associate with the periphery of neuronal nuclei. Run-on transcription studies utilizing [α-32P]-uridine triphosphate incorporation into newly synthesized total RNA further indicates that human neuronal-glial (HNG) cells in primary co-culture incubated with LPS exhibit significantly reduced output of DNA transcription products. These studies suggest that in AD LPS may impair the efficient readout of neuronal genetic information normally required for the homeostatic operation of brain cell function and may contribute to a progressive disruption in the read-out of genetic information.
Highlights
IntroductionTHE HUMAN GI TRACT MICROBIOMEThe human gastrointestinal (GI) tract microbiome is comprised of a complex and dynamic community of microbiota consisting predominantly of bacteria with various species of fungi, protozoa, viruses and other microorganisms making up the balance (Lukiw, 2016a,b; Pistollato et al, 2016; Zhan et al, 2016; Jiang Q. et al, 2017; Sherwin et al, 2017; Westfall et al, 2017).LPS Down-Regulates Transcription in Alzheimer’s disease (AD)The number of GI tract microbial genes from 1000 different species of anaerobic or facultative anaerobic bacteria vastly outnumber human genes by at least one hundred to one (Foster et al, 2016; Lukiw, 2016a,b; Zhan et al, 2016; Jiang Q. et al, 2017; McManus and Heneka, 2017; Zhao et al, 2017a,b)
In order to investigate how LPS may be associating with neuronal nuclei, a series of temporal lobe neocortical sections from control and age-matched Alzheimer’s disease (AD) brains were stained with LPS and a DAPI nuclear stain as well as the neuron-specific stain NeuN; the results of two control brains and two AD brains are representative of assays on multiple brains (N = 12)
In AD LPS accumulation was associated with the nuclei of neurons; in moderate-to-late-stage AD some neuronal nuclei were almost completely surrounded by LPS
Summary
THE HUMAN GI TRACT MICROBIOMEThe human gastrointestinal (GI) tract microbiome is comprised of a complex and dynamic community of microbiota consisting predominantly of bacteria with various species of fungi, protozoa, viruses and other microorganisms making up the balance (Lukiw, 2016a,b; Pistollato et al, 2016; Zhan et al, 2016; Jiang Q. et al, 2017; Sherwin et al, 2017; Westfall et al, 2017).LPS Down-Regulates Transcription in ADThe number of GI tract microbial genes from 1000 different species of anaerobic or facultative anaerobic bacteria vastly outnumber human genes by at least one hundred to one (Foster et al, 2016; Lukiw, 2016a,b; Zhan et al, 2016; Jiang Q. et al, 2017; McManus and Heneka, 2017; Zhao et al, 2017a,b). Run-on transcription studies of human neuronalglial (HNG) cells in primary culture using an extremely sensitive endogenous RNA Pol II activity driven incorporation of [α-32P]uridine triphosphate (108 dpm/ml) into newly synthesized total RNA indicated that nanomolar concentrations of LPS strongly inhibit neuronal nuclei transcriptional output. This may contribute in part to the generalized down-regulation of gene expression for transcription factors and synaptic and neurotrophic markers as is widely observed in sporadic AD brain (Colangelo et al, 2002; Ginsberg et al, 2012; Garcia-Esparcia et al, 2017; Itoh and Voskuhl, 2017)
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