Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer's disease.

Paul D Wes,Nestor X Barrezueta,Stefanie Keenan,Amy Truong,Aiqing He,Donna M Barten,Lynn B Decarr,Craig Polson,Nino Devidze,Marianne E Flynn,Amy Easton,Regina Lidge,Clotilde Bourin,Sethu Sankaranarayanan,Jere E Meredith ,Joanne E Natale ,John P Corradi ,Gregory Cadelina ,Charlie Albright ,Angela Cacace

doi:10.1371/journal.pone.0106050

Paul D Wes, Nestor X Barrezueta + Show 18 more

Open Access

https://doi.org/10.1371/journal.pone.0106050

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Journal: PloS one	Publication Date: Aug 25, 2014
Citations: 93	License type: CC BY 4.0

Affiliation: Bristol-Myers Squibb (United States)

Abstract

Filamentous inclusions of the microtubule-associated protein, tau, define a variety of neurodegenerative diseases known as tauopathies, including Alzheimer’s disease (AD). To better understand the role of tau-mediated effects on pathophysiology and global central nervous system function, we extensively characterized gene expression, pathology and behavior of the rTg4510 mouse model, which overexpresses a mutant form of human tau that causes Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We found that the most predominantly altered gene expression pathways in rTg4510 mice were in inflammatory processes. These results closely matched the causal immune function and microglial gene-regulatory network recently identified in AD. We identified additional gene expression changes by laser microdissecting specific regions of the hippocampus, which highlighted alterations in neuronal network activity. Expression of inflammatory genes and markers of neuronal activity changed as a function of age in rTg4510 mice and coincided with behavioral deficits. Inflammatory changes were tau-dependent, as they were reversed by suppression of the tau transgene. Our results suggest that the alterations in microglial phenotypes that appear to contribute to the pathogenesis of Alzheimer’s disease may be driven by tau dysfunction, in addition to the direct effects of beta-amyloid.

Highlights

Filamentous inclusions of the microtubule-associated protein, tau, define a variety of neurodegenerative diseases called tauopathies [1]
One outlier was identified and excluded from all analysis. Both age and genotype contributed to variation in the dataset, including large differences between the tTA and DN controls. tTA littermates were chosen as the key control, since this genotype differs from rTg4510 only by the presence of the tau transgene. 1,523 and 2,749 probe sets showed altered expression between rTg4510 and tTA mice at 4.7 months and 6.1 months, respectively (Fisher’s Least Significant Difference test between rTg4510 and tTA mice at each age, False Discovery Rate, FDR, 0.05); 447 probe sets showered altered expression in rTg4510 animals as they aged from 1.9 to 6.1 months
Elevated levels of phosphorylated tau and neurofibrillary tangles lead to neurotoxicity, cognitive deficits, and behavioral symptoms in the class of neurodegenerative disorders collectively called tauopathies

Summary

Introduction

Filamentous inclusions of the microtubule-associated protein, tau, define a variety of neurodegenerative diseases called tauopathies [1]. A similar immune function network was independently identified in AD and shown to correlate with DNA variants as well as amyloid pathology [13,14], and included genes genetically associated with AD risk [15,16,17,18,19]. These results imply that the immune gene expression network associated with AD contributes to the etiology of the disease–or at least provides a permissive environment in which the disease can progress–rather than representing a secondary response to pathology and neuronal damage [20]

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