What's the science?
Alzheimer’s disease has previously been associated with various bacteria and viruses — in particular herpes simplex virus. However, the mechanism by which viruses may contribute to Alzheimer’s disease is not clear. This week in Neuron, Readhead and colleagues used a neuropathological network model (at the gene, transcription, protein, and histopathology levels) to understand the contribution of viruses to Alzheimer’s.
How did they do it?
The authors obtained data from brains (after death) of healthy individuals, those with ‘pre-clinical’ Alzheimer’s (i.e. early, visible pathology but no cognitive impairment at time of death), and those with later stage Alzheimer’s disease. They first used computational modelling (they created probabilistic causal networks) to understand the differences in gene expression networks between healthy individuals and those with pre-clinical Alzheimer’s disease. They focused analyses on the entorhinal cortex and hippocampus (two regions affected by the disease). From the pre-clinical and control groups, they found genes they referred to as ‘network drivers’ that regulated a large portion of the gene expression in the network.
They then evaluated viral activity (viral RNA and DNA sequences) in patients with clinical Alzheimer’s (four independent cohorts) versus healthy controls. They first performed RNA sequencing in tissue from the superior temporal gyrus, anterior prefrontal cortex, inferior frontal gyrus, and parahippocampal gyrus obtained from one of the four cohorts, and looked for the presence of genes associated with viruses known to infect the human transcriptome. They also performed whole-exome sequencing to assess viral DNA in the same regions. The relationship between Alzheimer’s traits (Clinical Dementia Rating, Amyloid Plaque Density) and elevated viral RNA and DNA levels was also examined.
What did they find?
When the authors assessed pre-clinical Alzheimer’s versus healthy control gene networks, they found that promoters (i.e. the region of the gene that turns on transcription) for gene network drivers lost or gained in pre-clinical Alzheimer’s were enriched for C2H2 zinc factor transcription factor binding motifs. The “lost in pre-clinical Alzheimer’s disease” drivers had more G-quadruplex motifs within their genes. There was also a negative relationship between the density of G-quadruplex (co-regulatory with C2H2 transcription factor) and the expression of these genes in the entorhinal cortex in the pre-clinical Alzheimer’s and Alzheimer’s disease samples. These types of changes have been previously associated with viral biology/viral infection, suggesting that viral activity is associated with Alzheimer’s. As a second line of evidence, they found overlap between identified gene network drivers and gene targets of human microRNAs that had been previously associated with innate immunity and DNA viral activity.
When the authors assessed viral abundance in the brains of patients with Alzheimer’s, they found increased viral species in the anterior prefrontal cortex and superior temporal gyrus; in particular, HHV-7 and HHV-6A (i.e. herpesviruses). These elevated levels were also found in other brain regions in two additional cohorts of patients, suggesting that these viruses are increased across different tissues. The same findings were not present in samples of pathological aging or progressive supranuclear palsy (another neurodegenerative disorder), suggesting they are specific to Alzheimer’s. Increased viral DNA for HHV-6A was also detected. An HHV-7 gene and HHV-6A region were associated with Alzheimer’s traits (dementia ratings & plaque density) and viral abundance mediated gene expression of genes involved in disease risk and beta-amyloid processing (which form plaques). They also identified that some host genes (in particular the MIR155 host gene) regulated by HHV-6A (a herpesvirus) could form a network associated with neuronal loss, indicating that HHV-6A may be implicated in neurodegeneration. Finally, the authors performed some follow-up analyses in mice and found that MIR155 knockout mice had larger cortical amyloid plaques. Upregulated genes in MIR155 knockout mice were similar to those upregulated by the HHV-6A virus, suggesting that HHV-6A could act by inhibiting MIR155.
What's the impact?
This study provides genetic, clinical, and neuropathological evidence that there may be viral and host factors that interact to contribute to Alzheimer’s pathology. Viruses could potentially disturb biological processes (e.g. leading to plaque formation) or alter transcription or regulatory mechanisms. The contribution of viral activity in Alzheimer’s should be further investigated.
Readhead et al., Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron (2018). Access the original scientific publication here.