Abstract: OBJECTIVE To assess the effect of Haowang Formula (HWF) in treating Alzheimer's disease (AD) cognitive impairment using scopolamine mice model and senescence accelerated mice P8 (SAMP8) model， and investigated the underlying mechanism centered on PKA-mediated clearance of phosphorylated TAU and enhancement of synaptic plasticity. METHODS Mice were randomly divided into 4 groups in both models: Control group（CTL）， Model group (Veh)， Haowang Formula group and Donepezil group (Donepezil). Morris water maze (MWM) and novel object recognition test (NOR) were used to evaluate the cognitive ability of mice. Western Blot was used to detect the protein levels in PKA-GSK3β-TAU， PKA-CREB and its downstream molecule BDNF and synaptic proteins including SYNAPSIN1， GLUR1， and PSD95 in the hippocampus of SAMP8. RESULTS Under scopolamine model， compared to Model group， HWF and Donepezil distinctly improved times of crossing the platform in Morris water maze. Under SAMP8 model， both HWF and donepezil displayed therapeutic effect on escape latency and times of crossing the platform in MWM， and new object recognition index in NOR （P<0.01）. However， HWF increased distance in target quadrant and showed better treatment effect on shortening escape latency than donepezil （P<0.01）. In hippocampus of SAMP8 mice， HWF distinctly reduced the protein levels of TAU-ser404 by activating PKA-GSK3β-TAU pathway （P<0.01）. It also reversed the down-regulation of PKA-CREB and its downstream molecule BDNF and synaptic proteins including SYNAPSIN1， GLUR1， and PSD95 （P<0.05，P<0.01）. CONCLUSION HWF can improve cognitive impairment in AD mice models， which is related to PKA-mediated clearance of phosphorylated TAU and enhancement of synaptic plasticity.