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/EBP beta) activity was observed in hTau-overexpressing cells and the hippocampus of the AD patients, while downregulating C/EBP beta by siRNA abolished the hTau-induced TRPC1 upregulation. These data reveal that increasing intracellular tau can upregulate C/EBP beta-TRPC1-SOCE signaling and thus disrupt phosphorylating system, which together aggravates tau pathologies leading to a chronic neurodegeneration.