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.