Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology

Matthew J Simon,Jeffrey J Iliff,Randall L Woltjer,Charles F Murchison,Erin L Boespflug,Natalie E Roese,Marie X Wang

doi:10.1038/s41598-018-30779-x

Matthew J Simon, Jeffrey J Iliff + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-30779-x

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Journal: Scientific Reports	Publication Date: Aug 17, 2018
Citations: 45	License type: open-access

Affiliation: Oregon Health & Science University

Abstract

The deposition of misfolded proteins, including amyloid beta plaques and neurofibrillary tangles is the histopathological hallmark of Alzheimer’s disease (AD). The glymphatic system, a brain-wide network of perivascular pathways that supports interstitial solute clearance, is dependent upon expression of the perivascular astroglial water channel aquaporin-4 (AQP4). Impairment of glymphatic function in the aging rodent brain is associated with reduced perivascular AQP4 localization, and in human subjects, reduced perivascular AQP4 localization is associated with AD diagnosis and pathology. Using human transcriptomic data, we demonstrate that expression of perivascular astroglial gene products dystroglycan (DAG1), dystrobrevin (DTNA) and alpha-syntrophin (SNTA1), are associated with dementia status and phosphorylated tau (P-tau) levels in temporal cortex. Gene correlation analysis reveals altered expression of a cluster of potential astrocytic endfoot components in human subjects with dementia, with increased expression associated with temporal cortical P-tau levels. The association between perivascular astroglial gene products, including DTNA and megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) with AD status was confirmed in a second human transcriptomic dataset and in human autopsy tissue by Western blot. This suggests changes in the astroglial endfoot domain may underlie vulnerability to protein aggregation in AD.

Highlights

Aggregation of mis-folded proteins is a central hallmark of numerous neurodegenerative diseases
Using Weighted Gene Co-expression Network Analysis (WGCNA), we identify a cluster of 11 astrocytic genes that have similar gene expression profiles with dystrophin-associated complex (DAC) genes and AQP4 in the aging brain, and whose expression levels predict dementia status and are strongly associated with temporal cortical tau pathology
We confirm the associations between the newly identified genes and Alzheimer’s disease (AD) pathology at both the gene expression and protein levels in independent human AD cohorts. These findings suggest that changes in perivascular astroglial function may be one factor contributing to the development of AD pathology

Summary

Introduction

Aggregation of mis-folded proteins is a central hallmark of numerous neurodegenerative diseases. Using Weighted Gene Co-expression Network Analysis (WGCNA), we identify a cluster of 11 astrocytic genes that have similar gene expression profiles with DAC genes and AQP4 in the aging brain, and whose expression levels predict dementia status and are strongly associated with temporal cortical tau pathology.

Results

Conclusion