Abstract
The remarkable co-localization of highly pro-inflammatory lipopolysaccharide (LPS) with sporadic Alzheimer’s disease (AD)-affected neuronal nuclei suggests that there may be some novel pathogenic contribution of this heat stable neurotoxin to neuronal activity and neuron-specific gene expression. In this communication we show for the first time: (i) the association and envelopment of sporadic AD neuronal nuclei with LPS in multiple AD neocortical tissue samples; and (ii) a selective repression in the output of neuron-specific neurofilament light (NF-L) chain messenger RNA (mRNA), perhaps as a consequence of this association. The down-regulation of NF-L mRNA and protein is a characteristic attribute of AD brain and accompanies neuronal atrophy and an associated loss of neuronal architecture with synaptic deficits. To study this phenomenon further, human neuronal-glial (HNG) cells in primary culture were incubated with LPS, and DNA arrays, Northern, Western, and ELISA analyses were used to quantify transcription patterns for the three member neuron-specific intermediate filament-gene family NF-H, NF-M, and NF-L. As in sporadic AD limbic-regions, down-regulated transcription products for the NF-L intermediate filament protein was significant. These results support our novel hypothesis: (i) that internally sourced, microbiome-derived neurotoxins such as LPS contribute to a progressive disruption in the read-out of neuron-specific genetic-information; (ii) that the presence of LPS-enveloped neuronal nuclei is associated with a down-regulation in NF-L expression, a key neuron-specific cytoskeletal component; and (iii) this may have a bearing on progressive neuronal atrophy, loss of synaptic-contact and disruption of neuronal architecture, all of which are characteristic pathological features of sporadic-AD brain. This is the first report that provides evidence for a neuron-specific effect of a human GI-tract microbiome-derived neurotoxin on decreased NF-L abundance in both sporadic AD temporal lobe neocortex in vivo and in LPS-stressed HNG cells in vitro.
Highlights
There has been a resurgence of interest in the human gastrointestinal (GI) tract microbiome and its potential contribution to human health and disease
We adopted the strategy that because inter-synaptic connections, the radial diameter of neurons and the overall neuronal architecture and morphology are maintained in large part by this relatively abundant three member neuron-specific neurofilament gene family – encoding the neurofilament light (NF-L; NEFL; 68 kDa), neurofilament medium (NF-M; ∼160 kDa), and neurofilament heavy (NF-H; ∼205 kDa) chain proteins – we reasoned that NF-L, NF-M, and NF-H relative abundance would be an experimentally practical and suitable choice to look for changes in expression in both sporadic Alzheimer’s disease (AD) brain and in LPS treated human neuronal-glial (HNG) cells in primary culture
Our findings indicate for the first time, that linked to a progressive association of the amphiphilic glycolipid LPS with sporadic AD neuronal nuclei there appears to be a parallel and selective repression in the output of neuron-specific NFL mRNA in AD brain compared to age-and gender-matched controls
Summary
There has been a resurgence of interest in the human gastrointestinal (GI) tract microbiome and its potential contribution to human health and disease. Several recent papers have addressed the emerging link between elements of the human GI-tract microbiome and Alzheimer’s disease (AD), a common, chronic, and progressive age-related neurodegenerative disease whose incidence is reaching epidemic proportions and represents a major, lethal, neuropsychiatric disorder that currently constitutes a major healthcare concern worldwide (Zhan et al, 2016; Jiang et al, 2017; Cox and Weiner, 2018; Szablewski, 2018; Zhao and Lukiw, 2018) Both the familial and the much more common sporadic forms of AD are characterized by the appearance of extracellular deposits including dense, insoluble amyloid-beta (Aβ) peptide enriched senile plaques (SP) and tau- and neurofilament-protein enriched neurofibrillary tangles (NFT), and neuropathologically by the progressive atrophy of large neurons, ensuing loss of synaptic contacts and altered neuronal cytoarchitecture (Clark and Vissel, 2015; Zhao and Lukiw, 2015; Minter et al, 2016). We adopted the strategy that because inter-synaptic connections, the radial diameter of neurons and the overall neuronal architecture and morphology are maintained in large part by this relatively abundant three member neuron-specific neurofilament gene family – encoding the neurofilament light (NF-L; NEFL; 68 kDa), neurofilament medium (NF-M; ∼160 kDa), and neurofilament heavy (NF-H; ∼205 kDa) chain proteins – we reasoned that NF-L, NF-M, and NF-H relative abundance would be an experimentally practical and suitable choice to look for changes in expression in both sporadic AD brain and in LPS treated human neuronal-glial (HNG) cells in primary culture
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