Transcriptional Signatures of Tau and Amyloid Neuropathology

• Published in: Cell reports (Cambridge) Vol. 30; no. 6; pp. 2040 - 2054.e5
• Main Authors: Castanho, Isabel, Murray, Tracey K., Hannon, Eilis, Jeffries, Aaron, Walker, Emma, Laing, Emma, Baulf, Hedley, Harvey, Joshua, Bradshaw, Lauren, Randall, Andrew, Moore, Karen, O’Neill, Paul, Lunnon, Katie, Collier, David A., Ahmed, Zeshan, O’Neill, Michael J., Mill, Jonathan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.02.2020; Cell Press; Elsevier
• Subjects: Alzheimer Disease - genetics; Alzheimer’s disease; amyloid; Amyloid beta-Peptides - adverse effects; Animals; Disease Models, Animal; Disease Progression; entorhinal cortex; gene expression; hippocampus; Humans; Mice; Mice, Transgenic; neuropathology; RNA-seq; tau; tau Proteins - adverse effects; transgenic model; transgenic model; amyloid; Alzheimer’s disease; hippocampus; RNA-seq; tau; entorhinal cortex; gene expression; neuropathology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.01.063

Alzheimer’s disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of β-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progression of tau and amyloid pathology. rTg4510 mice are characterized by widespread transcriptional differences in the entorhinal cortex with changes paralleling neuropathological burden across multiple brain regions. Differentially expressed transcripts overlap with genes identified in genetic studies of familial and sporadic AD. Systems-level analyses identify discrete co-expression networks associated with the progressive accumulation of tau that are enriched for genes and pathways previously implicated in AD pathology and overlap with co-expression networks identified in human AD cortex. Our data provide further evidence for an immune-response component in the accumulation of tau and reveal molecular pathways associated with the progression of AD neuropathology. [Display omitted] •Mice with human tau and amyloid mutations develop progressive neuropathology•We identify transcriptional changes associated with tau and amyloid pathology•Discrete co-expression networks are associated with the progression of tau pathology•These are enriched for genes and pathways implicated in the onset of human AD Castanho et al. use transgenic mice harboring human tau and amyloid precursor protein mutations to identify transcriptional changes associated with the progression of Alzheimer’s disease (AD) pathology. Their data support an immune-response component in the accumulation of tau and reveal molecular pathways associated with AD neuropathology.