Docosahexaenoic acid ameliorates traumatic brain injury involving JNK-mediated Tau phosphorylation signaling

Highlights

• TBI induction leads to increased phosphorylation of JNK and Tau.

• DHA suppresses TBI induced JNK and Tau hyperphosphorylation.

• DHA rescues learning and memory deficits and improves motor function.

Abstract

Hyperphosphorylation of Tau has been found in patients with traumatic brain injury (TBI). Inhibition of c-Jun N-terminal kinases (JNKs) improves neurological function by suppressing Tau phosphorylation. By inhibiting JNK, docosahexaenoic acid (DHA) protects against cognitive decline in a mouse model of Alzheimer’s disease (AD). We hypothesize that DHA protects against neuronal damage and behavioral deficits by inhibition of JNK mediated Tau phosphorylation. We induced TBI in mice and examined the phosphorylation status of JNK and Tau. We treated TBI and sham operated mice with DHA, and investigated the effects of DHA on JNK and Tau phosphorylation, hippocampal long term potentiation (LTP), learning and memory, and motor function by Western blot analysis, electrophysiology recording and behavioral assessments including Morris water maze test, beam-balance test, beam-walk test and rotarod test. We found that TBI induction lead to increased phosphorylation of JNK and Tau. DHA suppressed TBI induced JNK and Tau hyperphosphorylation, rescued TBI mediated hippocampal LTP deficits and hippocampus dependent learning and memory dysfunction, and improved motor function. Inhibition of JNK and Tau phosphorylation by DHA may represent a potential therapeutic strategy for TBI induced neurological dysfunction and Tauopathy.

Introduction

Traumatic brain injury (TBI), a major cause of premature death and disability, leads to cognitive impairment and motor dysfunction. In addition to acute neuronal damage, TBI also induces long term adverse influences to brain function. TBI is a risk factor for neurodegenerative diseases, including Alzheimer’s disease (AD). One histopathological manifestation of AD is the presence of neurofibrillary tangles containing hyperphosphorylated Tau. It has been shown that TBI leads to hyperphosphorylation of Tau. Elevated Tau protein levels were found in cerebral spinal fluid and serum during postmortem examination following head injury (Olczak et al., 2017). Additionally, elevated Tau phosphorylation, total Tau and phosphorylated Tau to total Tau ratio were also found in patients with acute TBI compared to controls (Rubenstein et al., 2017).

Among the kinases that drive Tau phosphorylation, c-Jun N-terminal kinases (JNKs) are implicated in AD pathogenesis and have been shown to play a critical role in driving hyperphosphorylation of Tau in AD animal models and in vitro cell culture systems (Ploia et al., 2011). Activation of JNKs has been detected in the brain tissue of AD patients and blocking JNK activity reduces Tau phosphorylation.

Recent studies have shown that activation of JNK is also associated with TBI pathogenesis. Induction of TBI in mice by a craniotomy-weight drop method leads to increased JNK phosphorylation, the active form of JNK (Rehman et al., 2018). Inhibition of JNK by SP600125, a specific JNK inhibitor, significantly alleviated brain damage and improved cognitive function including learning and memory in mice with TBI (Rehman et al., 2018). When examining the subcellular localization of JNK activation following TBI, Tran et al. found that activated JNK was highly enriched in injured axons (Tran et al., 2012). Remarkably, JNK activation coincided with Tau phosphorylation in these axons and reduction of JNK activity suppressed accumulation of phosphorylated Tau in a mouse model of TBI.

Docosahexaenoic acid (DHA) is a marine n-3 polyunsaturated fatty acid that is abundantly expressed in human brain and has been shown to be associated with cognitive function (McCann and Ames, 2005). By inhibition of JNK, DHA selectively inhibits cognitive deficits in a mouse model of AD (Vela et al., 2019). Although the connection between DHA and JNK has not been extensively studied in TBI, DHA administration and inhibition of JNK have been shown to be beneficial to brain function respectively in subjects under TBI induction. Previously we have shown that DHA provides neuroprotective roles including reduced neuronal loss and brain damage and improved spatial learning and memory in rats with TBI (Zhu et al., 2017, 2018). Therefore, we hypothesized that DHA protects against TBI induced brain damage through inhibition of JNK mediated Tau phosphorylation.

In the current study, we investigated this hypothesis by examination of JNK and Tau phosphorylation in the presence or absence of DHA treatment in a mouse model of TBI. We further explored the beneficial effects of DHA in hippocampal dependent neurological functions and other motor functions.