Tau-induced upregulation of C/EBPβ-TRPC1-SOCE signaling aggravates tauopathies: A vicious cycle in Alzheimer neurodegeneration.
Jinwang YeYing YinYa-Ling YinHuaqiu ZhangHuali WanLu WangYue ZuoDi GaoMengzhu LiJun LiYanchao LiuDan KeJian-Zhi WangPublished in: Aging cell (2020)
Intracellular accumulating of the hyperphosphorylated tau plays a pivotal role in neurodegeneration of Alzheimer disease (AD), but the mechanisms underlying the gradually aggravated tau hyperphosphorylation remain elusive. Here, we show that increasing intracellular tau could upregulate mRNA and protein levels of TRPC1 (transient receptor potential channel 1) with an activated store-operated calcium entry (SOCE), an increased intraneuronal steady-state [Ca2+ ]i , an enhanced endoplasmic reticulum (ER) stress, an imbalanced protein kinases and phosphatase, and an aggravated tauopathy. Furthermore, overexpressing TRPC1 induced ER stress, kinases-phosphatase imbalance, tau hyperphosphorylation and cognitive deficits in cultured neurons and mice, while pharmacological inhibiting or knockout TRPC1 attenuated the hTau-induced deregulations in SOCE, ER homeostasis, kinases-phosphatase balance, and tau phosphorylation level with improved synaptic and cognitive functions. Finally, an increased CCAAT-enhancer-binding protein (C/EBPβ) activity was observed in hTau-overexpressing cells and the hippocampus of the AD patients, while downregulating C/EBPβ by siRNA abolished the hTau-induced TRPC1 upregulation. These data reveal that increasing intracellular tau can upregulate C/EBPβ-TRPC1-SOCE signaling and thus disrupt phosphorylating system, which together aggravates tau pathologies leading to a chronic neurodegeneration.
Keyphrases
- cerebrospinal fluid
- binding protein
- high glucose
- diabetic rats
- endoplasmic reticulum
- vascular smooth muscle cells
- drug induced
- endothelial cells
- type diabetes
- end stage renal disease
- reactive oxygen species
- newly diagnosed
- ejection fraction
- chronic kidney disease
- adipose tissue
- peritoneal dialysis
- gene expression
- small molecule
- climate change
- risk assessment
- electronic health record
- long non coding rna
- cognitive impairment
- spinal cord injury
- angiotensin ii
- drug delivery