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

• Published in: Aging cell Vol. 19; no. 1; pp. e13055 - n/a
• Main Authors: Ye, Jinwang, Yin, Yaling, Liu, Huanhuan, Fang, Lin, Tao, Xiaoqing, Wei, Linyu, Zuo, Yue, Yin, Ying, Ke, Dan, Wang, Jian‐Zhi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-01-2020; John Wiley and Sons Inc
• Subjects: Alzheimer's disease; Brain-derived neurotrophic factor; Cognitive ability; CREB; CREB-Binding Protein - metabolism; Cyclic adenylic acid; Cyclic AMP response element-binding protein; Cyclic AMP-Dependent Protein Kinases - drug effects; Dephosphorylation; GluA1; Humans; Kinases; Memory; mRNA; Neurodegenerative diseases; Neuronal Plasticity - genetics; Original; PA28γ; Phosphorylation; PKA; proteasome; Proteasome activator; Protein binding; Protein kinase A; Protein kinases; Proteins; RNA; Signal Transduction; Synapses - metabolism; synaptic plasticity; Tau; Tau protein; tau Proteins - metabolism; TrkB receptors; proteasome; CREB; PKA; PA28γ; Tau; GluA1; synaptic plasticity
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13055

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.
Tau overexpressed decreases the formation of PA28γ‐20S proteasome complex by increasing the association of PKAR2α (an inhibitory subunit of PKA) with PA28γ (a nuclear proteasome activator), which leads to reduced PKAR2α degradation in ubiquitin‐independent proteasome degradation pathway mediated by PA28γ‐20S proteasome complex. PKA inhibition by elevated PKAR2α in nuclear fraction finally induces synapse impairments and memory deficits by inhibiting PKA/CREB/BDNF/TrkB and PKA/GluA1 signaling.