To explore the correlation between cerebral functional alterations revealed by functional magnetic resonance imaging (fMRI) and Alzheimer disease- (AD)-like tau hyperphosphorylation, we injected bilaterally 2 μl each of 20 mM isoproterenol (IP), a PKA activator, or of saline as a vehicle control into the hippocampus of rats. FMRI was employed to measure the intensity of BOLD signal, one of the cerebral functional markers reflecting the changes of cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF), in hippocampus and cortex 24 h after the operation. Immunohistochemical staining of hippocampus and cortex was carried out using phosphorylation-dependent tau antibodies. The results showed (1) that BOLD intensity in hippocampus and cortex of IP-injected rats was obviously lower than that of sham-operated group, indicating a decrease in CMRO2 and CBF of the particular brain regions in IPtreated rats; (2) that tau was hyperphosphorylated at Ser-262 / Ser-356 (12e8), Ser-396 / Ser-404 (PHF-1) sites in CA1 CA2 CA3 CA4 and dentate gyrus regions of hippocampal formation and cortex area in IP group, but not in sham rats; (3) that a negative correlation between tau hyperphosphorylation and BOLD intensity in hippocampus and cortex area of IP rats was observed. The data suggested that hippocampal and cortical tau hyperphosphorylation was intimately related to BOLD intensity of the same areas. To our knowledge, this is the first report exploring the relationship between fMRI BOLD signal and AD-like tau hyperphosphorylation.