Abstract
SUMMARYAging and neurodegenerative disease are characterized by genomic instability in neurons, including aberrant activation and mobilization of transposable elements (TEs). Integrating studies of human postmortem brain tissue and Drosophila melanogaster models, we investigate TE activation in association with Tau pathology in Alzheimer’s disease (AD). Leveraging RNA sequencing from 636 human brains, we discover differential expression for several retrotransposons in association with neurofibrillary tangle burden and highlight evidence for global TE transcriptional activation among the long interspersed nuclear element 1 and endogenous retrovirus clades. In addition, we detect Tau-associated, active chromatin signatures at multiple HERV-Fc1 genomic loci. To determine whether Tau is sufficient to induce TE activation, we profile retrotransposons in Drosophila expressing human wild-type or mutant Tau throughout the brain. We discover heterogeneous response profiles, including both age- and genotype-dependent activation of TE expression by Tau. Our results implicate TE activation and associated genomic instability in Tau-mediated AD mechanisms.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia, with more than 13 million individuals projected to be affected in the United States by 2050 (Querfurth and LaFerla, 2010)
Tau Pathologic Burden Is Associated with Altered transposable elements (TEs) Expression in Human Brains To examine whether AD neurofibrillary tangle pathology is associated with TE activation, we first leveraged data from 2 prospective human clinical-pathologic studies, the Religious Orders Study and Rush Memory and Aging Project (ROSMAP)
Current algorithms for building transcriptomes rely on alignment of RNA sequencing (RNA-seq) data to a genomic reference, in which most repetitive sequences derived from TEs are excluded
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia, with more than 13 million individuals projected to be affected in the United States by 2050 (Querfurth and LaFerla, 2010). Tau pathology is found in a heterogeneous group of neurodegenerative syndromes, the tauopathies, causing cognitive and/or motor impairment. Based on evidence from human postmortem material (Adamec et al, 1999) and animal models (Khurana et al, 2012), AD brain pathology is accompanied by genomic instability in affected neurons (Madabhushi et al, 2014), and Tau-mediated mechanisms are strongly implicated. In Drosophila, Tau induces global nuclear chromatin relaxation (Frost et al, 2014), abnormal transcriptional activation of heterochromatic genes, and DNA double-strand breaks (Khurana et al, 2012). Genetic manipulation of chromatin-modifying or DNA-repair pathways can suppress Tau neurotoxicity, suggesting that the maintenance of genomic integrity and neurodegeneration in AD may be causally linked rather than a downstream consequence of cell death
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