Alterations of transcriptome signatures in head trauma-related neurodegenerative disorders

Hyesun Cho,Hoon Ryu,Thor D Stein,Seung Jae Hyeon,Junghee Lee,Victor E Alvarez,Neil W Kowall,Jeong-Sun Seo,Jong-Yeon Shin,Ann C Mckee

doi:10.1038/s41598-020-65916-y

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is associated with repetitive traumatic brain injury (TBI). CTE is known to share similar neuropathological features with Alzheimer’s disease (AD), but little is known about the molecular properties in CTE. To better understand the neuropathological mechanism of TBI-related disorders, we conducted transcriptome sequencing analysis of CTE including AD and CTE with AD (CTE/AD) post-mortem human brain samples. Through weighted gene co-expression network analysis (WGCNA) and principal component analysis (PCA), we characterized common and unique transcriptome signatures among CTE, CTE/AD, and AD. Interestingly, synapse signaling-associated gene signatures (such as synaptotagmins) were commonly down-regulated in CTE, CTE/AD, and AD. Quantitative real-time PCR (qPCR) and Western blot analyses confirmed that the levels of synaptotagmin 1 (SYT1) were markedly decreased in CTE and AD compared to normal. In addition, calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), protein kinase C (PKC), and AMPA receptor genes that play a pivotal role in memory function, were down-regulated in head trauma-related disorders. On the other hand, up-regulation of cell adhesion molecules (CAMs) associated genes was only found in CTE. Our results indicate that dysregulation of synaptic transmission- and memory function-related genes are closely linked to the pathology of head injury-related disorder and AD. Alteration of CAMs-related genes may be specific pathological markers for the CTE pathology.

Highlights

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is associated with repetitive traumatic brain injury (TBI)
We found that astrocyte, 6 oligodendrocyte, microglia, and 12 endothelial-specific genes were commonly up-regulated in Chronic Traumatic Encephalopathy (CTE), CTE/Alzheimer’s disease (AD), and AD
CTE is a progressive neurodegenerative disorder that leads to behavior, mood, and memory dysfunction

Summary

Introduction

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is associated with repetitive traumatic brain injury (TBI). To better understand the neuropathological mechanism of TBI-related disorders, we conducted transcriptome sequencing analysis of CTE including AD and CTE with AD (CTE/AD) post-mortem human brain samples. Synapse signaling-associated gene signatures (such as synaptotagmins) were commonly down-regulated in CTE, CTE/AD, and AD. Our results indicate that dysregulation of synaptic transmission- and memory function-related genes are closely linked to the pathology of head injury-related disorder and AD. CTE symptoms, which include changes in cognition, mood, or behavior, start 8-10 years after the repeated, traumatic brain damage. In Stage I, discrete foci of hyperphosphorylated tau are localized around brain blood vessels that are mostly found in the lateral and frontal cortices. In Stage III, hyperphosphorylated tau pathology spreads to the frontal, temporal, parietal and insular cortices. Deposition of hyperphosphorylated tau and presence of NFTs are common neuropathological features of CTE and AD7. The relative contribution of other pathological substrates to clinical symptoms in CTE with other neuropathology is unknown

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