Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85287-5001, USA.
Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Neuron. 2018 Jul 11;99(1):64-82.e7. doi: 10.1016/j.neuron.2018.05.023. Epub 2018 Jun 21.
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.
研究人员长期以来一直怀疑致病性微生物可能导致阿尔茨海默病（AD）的发病和进展，尽管尚未提出明确的证据。这些发现是否代表因果关系，或者反映神经退行性变的机会性乘客，也很难解决。我们构建了与晚发性 AD 相关病毒组的多尺度网络，整合了来自人类死后组织的四个大脑区域的基因组、转录组、蛋白质组和组织病理学数据。我们观察到与对照组相比，AD 患者的人类疱疹病毒 6A（HHV-6A）和人类疱疹病毒 7（HHV-7）增加。这些结果在另外两个独立且地理位置分散的队列中得到了复制。我们观察到与病毒丰度和 APP 代谢调节剂相关的调节关系，包括 HHV-6A 诱导的 APBB2、APPBP2、BIN1、BACE1、CLU、PICALM 和 PSEN1。这项研究阐明了将分子、临床和神经病理学特征与病毒活性联系起来的网络，并且与病毒活性构成 AD 的一般特征一致。
