NEW YORK (GenomeWeb) – Based on network analyses spanning transcriptomic, genomic, and proteomic features of brain viromes in aging individuals with or without late-onset Alzheimer's disease (AD), a team led by researchers at the Icahn School of Medicine and Arizona State University has proposed potential ties between human herpesvirus (HHV) infection, amyloid precursor protein (APP) metabolism, and AD.
"This study represents a significant advancement in our understanding of the plausibility of the pathogen hypothesis of Alzheimer's," corresponding author Joel Dudley, a genetics, genomic sciences, and multi-scale biology researcher affiliated with the Icahn School of Medicine and the ASU-Banner Neurodegenerative Disease Research Center, said in a statement.
As they reported online today in Neuron, Dudley and his colleagues sequenced RNA in hundreds of postmortem brain samples, representing unaffected controls and preclinical AD cases, meaning symptom-free individuals with AD neuropathology. Their data revealed a dramatic over-representation of HHV-7 and HHV-6A strains in the preclinical AD endophenotype.
The team shored up this apparent association using data for individuals from additional cohorts of clinical AD cases and controls without AD pathology or symptoms. Network analyses based on whole-exome sequencing, liquid chromatography tandem mass spectrometry, and immunohistochemistry data, along with mouse model experiments, suggested that this association may stem from interactions between viral abundance, transcriptional regulators, and other modulators of APP metabolism.
Studies stretching back several decades have raised the possibility that microbial infections and the immune response mounted against them might contribute to the onset or progression of neurodegenerative conditions such as AD, the authors noted. Even so, they wrote, such research has been "suggestive of a viral contribution to AD, though findings offer little insight into potential mechanisms, and a consistent association with specific viral species has not emerged."
Using Mount Sinai Brain Bank samples, the team sequenced the RNA of 137 superior temporal gyrus, 213 anterior prefrontal cortex, 186 inferior frontal gyrus, and 107 parahippocampal gyrus brain samples from individuals with or without AD, identifying sequences associated with 515 viral species.
Along with a jump in HHV-6 and HHV-7 levels in the AD brain samples, compared to those from controls, the available host expression, clinical, viral DNA, quantitative trait locus, and other data fed into network analyses are supporting a potential role for HHV in AD, the researchers reported.
They saw a similar rise in HHV-6 and HHV-7 representation in dorsolateral prefrontal cortex or temporal cortex samples from hundreds more AD-affected individuals compared to controls, using RNA-seq data from the Religious Orders Study, Memory and Aging Project, and Mayo Temporal Cortex cohorts.
In addition, through a series of systems analyses, mouse knockout experiments, and other follow-up work, the team got hints that viruses such as HHV-6A may impact regulatory pathways modulating APP metabolic players such as APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 and neuronal loss-related microRNAs such as miR-155.
"Previous studies of viruses and Alzheimer's have always been very correlative. But we were able to do statistical causal inference testing and more sophisticated analysis, which allowed us to identify how the viruses are directly interacting with or co-regulating or being regulated by Alzheimer's genes," Dudley said in a statement.
"I don't think we can answer whether herpesviruses are a primary cause of Alzheimer's disease," he added. "But what's clear is that they're perturbing networks and participating in networks that directly accelerate the brain towards the Alzheimer's topology."
Dudley and his co-authors cautioned that the presence of HHV-6 in the blood alone is not likely to help in finding individuals with AD-related viral activity in the brain, owing to the "near universal seropositivity for HHV-6 in the general population."
"The integrated findings of this study suggest that AD biology is impacted by a complex constellation of viral and host factors acting across different timescales and physiological systems," they wrote. "This includes host mucosal defense and modulation of innate immune response by virus and host."