Tau inhibits PKA by nuclear proteasome-dependent PKAR2α elevation with suppressed CREB/GluA1 phosphorylation.

Jinwang Ye,Ying Yin,Huanhuan Liu,Jian‐Zhi Wang,Linyu Wei,Dan Ke,Yue Zuo,Xiaoqing Tao,Lin Fang,Yaling Yin

doi:10.1111/acel.13055

Abstract

Intraneuronal accumulation of wild‐type tau plays a key role in Alzheimer's disease, while the mechanisms underlying tauopathy and memory impairment remain unclear. Here, we report that overexpressing full‐length wild‐type human tau (hTau) in mouse hippocampus induces learning and memory deficits with remarkably reduced levels of multiple synapse‐ and memory‐associated proteins. Overexpressing hTau inhibits the activity of protein kinase A (PKA) and decreases the phosphorylation level of cAMP‐response element binding protein (CREB), GluA1, and TrkB with reduced BDNF mRNA and protein levels both in vitro and in vivo. Simultaneously, overexpressing hTau increased PKAR2α (an inhibitory subunit of PKA) in nuclear fraction and inactivated proteasome activity. With an increased association of PKAR2α with PA28γ (a nuclear proteasome activator), the formation of PA28γ‐20S proteasome complex remarkably decreased in the nuclear fraction, followed by a reduced interaction of PKAR2α with 20S proteasome. Both downregulating PKAR2α by shRNA and upregulating proteasome by expressing PA28γ rescued hTau‐induced PKA inhibition and CREB dephosphorylation, and upregulating PKA improved hTau‐induced cognitive deficits in mice. Together, these data reveal that intracellular tau accumulation induces synapse and memory impairments by inhibiting PKA/CREB/BDNF/TrkB and PKA/GluA1 signaling, and deficit of PA28γ‐20S proteasome complex formation contributes to PKAR2α elevation and PKA inhibition.

Highlights

Intracellular accumulation of the abnormally modified microtu bule‐associated protein tau is a hallmark pathology in the brain of Alzheimer's disease (AD) and the other tauopathies
By neuron‐specific overexpression of human full‐length wild‐type tau, we demonstrate in the present study that human tau (hTau) accumula tion inhibits protein kinase A (PKA)/cAMP‐response element binding protein (CREB) signaling with downregulation of multiple synapse‐ and memory‐associated proteins and GluA1‐containing AMPARs surface expression both in vitro and in vivo
Intracellular accumulation of hyperphosphorylated tau has been widely observed in neurodegenerative diseases, such as AD, pro gressive supranuclear palsy (PSP), corticobasal degeneration, Pick disease, Huntington disease, and frontotemporal dementia with par kinsonism‐17 (Wang & Mandelkow, 2016)

Summary

| INTRODUCTION

Intracellular accumulation of the abnormally modified microtu bule‐associated protein tau is a hallmark pathology in the brain of Alzheimer's disease (AD) and the other tauopathies. By Golgi staining in brain slices, we observed that rolipram treatment restored hTau‐induced reduction of spine density (Figure 4j,k) with attenuation of CREB These data indicate that proteasome inhibition at least contributes to the hTau‐induced nuclear elevation of PKAR2α, which in turn in hibits PKA/CREB/BDNF signaling. Overexpressing hTau increased PKAR2α‐PA28γ asso ciation and reduced PA28γ‐20S complex formation with decreased PKAR2α‐20S subunit interaction (Figure 6a–c), while the interaction of tau with PA28γ was not detected (Figure 6d) These data indicate that hTau accumulation may indirectly inhibit the ubiquitin‐inde pendent proteasome degradation of PKAR2α and inhibit PKA. The level of PA28γ was decreased in hTau‐overexpressing cells, and up regulating PA28γ attenuated hTau‐induced PKAR2α elevation and CREB dephosphorylation (Figure 6g,h, S3c,d) These data suggest that an impaired 20S‐PA28γ proteasome complex formation may underlie the hTau‐induced PKAR2α upregulation and PKA inhibition, and downregulating PKAR2α or upregulating proteasome rescues PKA/CREB signaling

| DISCUSSION

Findings

| MATERIALS AND METHODS