Abstract
SummaryAlzheimer’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.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and associated cognitive and functional decline (Scheltens et al, 2016)
In addition to the loss of synapses and neurons, AD involves two neuropathological hallmarks: (1) the formation of neurofibrillary tangles (NFTs) that result from the intracellular aggregation of hyperphosphorylated tau protein, a characteristic of other neurodegenerative disorders including frontotemporal dementia (FTD), and (2) the development of amyloid plaques, which are extracellular deposits composed mainly of b-amyloid (Ab) protein that have been the focus of extensive efforts in drug discovery
We identified a dramatic accumulation of tau pathology in both the hippocampus and entorhinal cortex (Figures 1A–1C)
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and associated cognitive and functional decline (Scheltens et al, 2016). In addition to the loss of synapses and neurons (manifesting as brain atrophy), AD involves two neuropathological hallmarks: (1) the formation of neurofibrillary tangles (NFTs) that result from the intracellular aggregation of hyperphosphorylated tau protein, a characteristic of other neurodegenerative disorders including frontotemporal dementia (FTD), and (2) the development of amyloid plaques, which are extracellular deposits composed mainly of b-amyloid (Ab) protein that have been the focus of extensive efforts in drug discovery These neuropathological signatures of AD have been relatively well described in post-mortem human brain tissue, their exact mechanistic role in disease onset and progression remains poorly understood (De Strooper and Karran, 2016). Most analyses to date have been undertaken on relatively small numbers of animals and have not attempted to directly relate transcriptional alterations to the progressive burden of pathology from multiple brain regions in the same mice
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