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Cell Rep. 2020 Feb 11;30(6):2040-2054.e5. doi: 10.1016/j.celrep.2020.01.063.

Transcriptional Signatures of Tau and Amyloid Neuropathology.

Author information

1
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
2
Eli Lilly & Co., Erl Wood Manor, Sunninghill Road, Windlesham GU20 6PH, UK.
3
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK. Electronic address: j.mill@exeter.ac.uk.

Abstract

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.

KEYWORDS:

Alzheimer’s disease; RNA-seq; amyloid; entorhinal cortex; gene expression; hippocampus; neuropathology; tau; transgenic model

Conflict of interest statement

Declaration of Interests T.K.M., Z.A., D.A.C., L.B., and M.J.O. were full-time employees of Eli Lilly & Company Ltd. at the time this work was performed. M.J.O. is currently an employee of AbbVie.

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