In this study, we reported the first near-infrared (NIR) ESIPT fluorescence probe of its kind capable of monitoring dynamic changes of endogenous BACE1, through introducing a lipophilic π-conjugated thiophene-bridge for extension to NIR wavelength range with enhancement of BBB penetrability, thus making a breakthrough in high-fidelity feedback on in vivo detection of BACE1 with remarkable binding affinity in the AD live brains. The gene discussed is BACE1; the disease is Alzheimer disease.