Functional dissection of Alzheimer’s disease brain gene expression signatures in humans and mouse models

Abstract

Human brain transcriptomes can highlight biological pathways associated with Alzheimer's disease (AD); however, challenges remain to link expression changes with causal triggers. We have examined 30 ADassociated, gene coexpression modules from human brains for overlap with 251 differentially-expressed gene sets from mouse brain RNA-sequencing experiments, including from models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus neurofibrillary tangle pathology and further reveal age-and sex-dependent expression signatures for AD progression. Human coexpression modules enriched for neuronal and/or microglial genes overlap broadly with signatures from mouse models of AD, Huntington's disease, Amyotrophic Lateral Sclerosis, and also aging. Several human AD coexpression modules, including those implicated in the unfolded protein response and oxidative phosphorylation, were not activated in AD models, but instead were detected following other, unexpected mouse genetic manipulations. Our results comprise a powerful, cross-species resource and pinpoint experimental models for diverse features of AD pathophysiology from human brain transcriptomes.

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

“…While aging has myriad systemic and cellular targets, one key emerging theme is the dysregulation of innate immune mechanisms leading to a systemic pro-inflammatory state, which has been termed "immunosenescence" or "inflamm-ageing" [58,59]. In our analysis, innate immune pathways were strongly enriched among both aging-and Tau-associated, differentially expressed genes, and this result is consistent with brain gene expression profiling in mouse models of healthy aging [23,60] and tauopathy [61,62]. Similarly, multiple transcriptome-and proteome-wide analyses of human postmortem brain from AD or other tauopathies, such as PSP, have identified evidence of dysregulated immune pathways [9][10][11]18], and similar signatures have been implicated in brains from aged individuals without known neurodegenerative disease [63,64].…”

“…Prior studies have profiled brain gene expression in Tau transgenic animals, including in flies [31,32,52] and mouse models [21,23,41]; however, none to our knowledge have longitudinally assessed both transcripts and proteins in parallel. Our analyses provide a glimpse of the dynamic regulatory crosstalk between the brain transcriptome and proteome that respond to brain injury, as in tauopathy.…”

“…While recent advances in mass-spectrometry permit deep surveys of protein expression, few studies have systematically profiled both the brain transcriptome and proteome in AD and related tauopathies [18,19].By contrast with studies of human postmortem tissue, transgenic animal models of tauopathy readily permit controlled experimental manipulations to (i) define age-dependent changes, (ii) isolate the specific impact of Tau, and (iii) definitively establish causation. For example, RNA-seq in mouse transgenic models of tauopathy have highlighted early upregulation of inflammatory processes and downregulation of synaptic function genes preceding behavioral phenotypes, and suggest Tau-specific impact on microglial and neuronal function [20][21][22][23]. Expression of human MAPT in the nervous system of the fruit fly, Drosophila melanogaster, recapitulates many key features of tauopathies, including misfolded/hyperphosphorylated Tau, age-dependent synaptic dysfunction and neuronal loss, and reduced survival [6,24].…”

A novel systems biology approach to evaluate mouse models of late-onset Alzheimer’s disease

“…Similar approaches have been used to characterize mouse models of neurodegenerative disease (6). Detailed cross-species analysis reveals a translational gap between animal models and human disease, as no existing models fully recapitulate pathologies associated with LOAD (7,8). New platforms to rapidly assess the translational relevance of new animal models of LOAD will allow efficient identification of the most promising preclinical models.…”

A Portal to Visualize Transcriptome Profiles in Mouse Models of Neurological Disorders

“…In a recent study [6], a large collection of mouse studies related to neurological disorders were collected and processed using a unified RNA-seq pipeline utilizing Amazon Web Services (AWS). The studies were collected from the GEO database and the Accelerating Medicines Partnership-Alzheimer’s Disease (AMP-AD) Knowledge portal and include nine neurological diseases, 14 cell types, and 251 mouse experiment-control comparisons (i.e., Differentially Expressed Genes (DEGs)).…”