Un nuevo estudio respalda la conexión entre virus del herpes y enfermedad de Alzheimer

Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus

Summary

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.

Figure 1

Multiomic Evaluation of Alzheimer’s Disease-Associated Virome

(A) This study was performed in two phases, an initial exploration into the earliest network changes associated with preclinical AD, which identified multiple shifts in network biology consistent with viral perturbations and prompted a systematic, multiomic evaluation of viral biology on larger datasets focused on clinical AD.

(B–E) Regulatory networks built across EC and HIP samples showed differences in gene drivers for preclinical AD versus control networks (B) including many AD associated genes (C), although drivers exclusive to each network shared functional characteristics, such as association with viral biology (D), and promoter enrichments for the same C2H2 zinc finger transcription factors binding motifs (E).

(F and G) G-quadruplex sequence motifs were strongly enriched in the promoters of the drivers “lost in preclinical AD,” and those “gained in preclinical AD” (F); however, drivers “lost in preclinical AD” had much higher G-Quadruplex density in introns, exons, and 3′-UTR (G).

(H) Genes with high G-Quadruplex density in these locations were uniformly downregulated in the EC of preclinical AD and AD samples, suggesting some significant alteration of G-Quadruplex regulation.

(I–L) To investigate the possibility of an AD-associated virome, we incorporated clinical, neuropathological, RNA, DNA, and proteomic data from individuals with clinical AD (and controls) (I) across four brain regions to identify and characterize viral activity associated with AD biology (J and K), highlighting Roseoloviruses HHV-6A and HHV7 (L).

Region abbreviations: EC, entorhinal cortex; HIP, hippocampus; MTG, medial temporal gyrus; PC, posterior cingulate cortex; SFG, superior frontal gyrus; VCX, visual cortex.