Common viral species frequently detected in normal, aging brain
Increased HHV-6A and HHV-7 in brains of subjects with Alzheimer’s disease (AD)
Findings were replicated in two additional, independent cohorts
Multiscale networks reveal viral regulation of AD risk, and APP processing genes
Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer’s disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD.
Important roles for microbes and antimicrobial defenses in the pathogenesis of Alzheimer’s disease (AD) have been postulated or evaluated for at least six decades, beginning with Sjögren in 1952 (Sjogren et al., 1952). “Slow virus” was one of the early names used for the illness that eventually came to be known as prion disease, referring to the hypothesis that conventional viruses might be capable of acting to cause not only acute encephalitis, but also a progressive neuronal destruction process that might engender less inflammation because of its slowly progressive nature (Sigurðsson, 1954). Measles (MV) is a conventional virus that can act through acute inflammatory and slow neurodegenerative processes, occasionally re-emerging as a fatal brain disease known as subacute sclerosing panencephalitis (SSPE) up to a decade after a typical acute MV infection (Murphy and Yunis, 1976).
Beginning with Crapper McLachlan in 1980 (Middleton et al., 1980), several investigators have proposed that AD is an SSPE-like illness, caused by a slow virus form of herpes simplex (Itzhaki, 2014). Hundreds of reports have associated AD with diverse bacterial and viral pathogens (Itzhaki et al., 2016, Mastroeni et al., 2018), most frequently implicating Herpesviridae (particularly HSV-1 [Lövheim et al., 2015a, Lövheim et al., 2015b], EBV, HCMV, and HHV-6 [Westman et al., 2017, Carbone et al., 2014]). The results of these studies, taken in aggregate, are 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.
Recent reports demonstrate that diverse classes of microbes can stimulate amyloid-beta (Aβ) aggregation and deposition as part of an intra-CNS anti-microbial innate immune response whereby the amyloidosis triggered by various microbes results in the coating of the infectious particles by the growing amyloid aggregate (Soscia et al., 2010, Kumar et al., 2016, Eimer et al., 2018). These microbes coated with aggregated Aβ become unable to interact with cell surfaces, thereby arresting the infectious process.
We designed this study to map and compare biological networks underlying two distinct AD-associated phenotypes using multiple independent datasets collected from human subjects. We began with a computational network characterization of a specific endophenotype of AD: brains meeting neuropathological criteria for AD from individuals who were cognitively intact at the time of death (Liang et al., 2010), which we refer to here as “preclinical AD” (Sperling et al., 2011). We presumed that a network model of preclinical AD (and its comparison with networks built from cognitively intact persons without neuropathology) might provide novel insights into the molecular context of neuropathology in the absence of clinical symptoms. Alternatively, since these individuals had eluded cognitive decline despite significant AD pathology, we reasoned that this might illuminate protective or resilience mechanisms. Functional genomic analysis of preclinical AD network alterations revealed multiple lines of evidence consistent with viral activity. We then directly evaluated viral activity in a multiscale network analysis of four large, multi-omic datasets (comprising samples from individuals with “clinical AD” as well as neuropathologically and cognitively normal controls) that included next generation sequencing data, enabling direct examination of viral DNA and RNA sequences.
This study presents novel evidence linking the activity of specific viruses with AD. This has been enabled by comprehensive molecular profiling of large patient cohorts, facilitating the integration of diverse biomedical data types into an expansive view spanning multiple disease stages, brain regions, and -omic domains. This has also allowed us to direct our analysis in an entirely data-driven manner and benefit from a form of data capable of implicating specific viral species. Our results offer evidence of complex viral activity in the aging brain, including changes specific to AD, particularly implicating Herpesviridae, HHV-6, and HHV-7. Taken together, these data provide compelling evidence that specific viral species contribute to the development of neuropathology and AD.
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