Distinct dual roles of p-Tyr42 RhoA GTPase in tau phosphorylation and ATP citrate lyase activation upon different Aβ concentrations

Kim Cuong Cap,Yeon-Joo Jung,Bo Young Choi,Seung Jae Hyeon,Jae-Gyu Kim,Jung-Ki Min,Rokibul Islam,Abu Jubayer Hossain,Won-Suk Chung,Sang Won Suh,Hoon Ryu,Jae-Bong Park

doi:10.1016/j.redox.2020.101446

Abstract

Both the accumulation of Amyloid-β (Aβ) in plaques and phosphorylation of Tau protein (p-Tau) in neurofibrillary tangles have been identified as two major symptomatic features of Alzheimer's disease (AD). Despite of critical role of Aβ and p-Tau in AD progress, the interconnection of signalling pathways that Aβ induces p-Tau remains elusive. Herein, we observed that a popular AD model mouse (APP/PS1) and Aβ-injected mouse showed an increase in p-Tyr42 Rho in hippocampus of brain. Low concentrations of Aβ (1 μM) induced RhoA-mediated Ser422 phosphorylation of Tau protein (p-Ser422 Tau), but reduced the expression of ATP citrate lyase (ACL) in the HT22 hippocampal neuronal cell line. In contrast, high concentrations of Aβ (10 μM) along with high levels of superoxide production remarkably attenuated accumulation of p-Ser422 Tau, but augmented ACL expression and activated sterol regulatory element-binding protein 1 (SREBP1), leading to cellular senescence. Notably, a high concentration of Aβ (10 μM) induced nuclear localization of p-Tyr42 Rho, which positively regulated NAD kinase (NADK) expression by binding to the NADK promoter. Furthermore, severe AD patient brain showed high p-Tyr42 Rho levels. Collectively, our findings indicate that both high and low concentrations of Aβ are detrimental to neurons via distinct two p-Tyr42 RhoA-mediated signalling pathways in Ser422 phosphorylation of Tau and ACL expression.

Highlights

Alzheimer's disease (AD), an age-related neurodegenerative disorder, is a major cause of dementia
It has been well known that nerve growth factor (NGF) induces neurite outgrowth from PC12 cells, but we found that Aβ markedly attenuated neurite outgrowth from PC12 cells even in the presence of NGF (Fig. 1A)
Soluble Aβ was injected to the hippocampus of mouse brain and allowed to diffuse, which stimulated hippocampus for 24 h. p-Tyr42 Rho was much increased in neurons of cornu ammonis 1 (CA1) and CA2 regions by 5 μl of 10 and 100 μM Aβ (Fig. 1D)

Summary

Introduction

Alzheimer's disease (AD), an age-related neurodegenerative disorder, is a major cause of dementia. The major pathological features of AD include extracellular senile plaques, consisting of amyloid-β (Aβ) peptide and intracellular neurofibrillary tangles (NFTs) consisting of aggregated hyperphosphorylated Tau protein. The accumulation of oligomeric and fibrillary Aβ contributes to hyperphosphorylation of the Tau protein through a series of neuronal signal transduction events [1]. Tau is a microtubule (MT) associated protein and involved in the Abbreviations: 8-oxoG, 8-oxoguanine; Aβ, amyloid beta peptide; ACL, ATP citrate lyase; AD, Alzheimer disease; DPI, diphenyleneiodonium chloride; GSK-3β, glycogen synthase kinase-3β; GFAP, glial fibrillary acidic protein (astrocyte marker); Iba, ionized calcium-binding adapter molecule 1 (microglia marker); NADK, NAD kinase; NeuN, neuronal nuclei specific antibody; NGF, nerve growth factor; ROCK, Rho-dependent coiled-coil kinase; ROS, reactive oxygen species; SREBP, sterol regulatory element-binding protein; mSREBP, matured SREBP

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