Fluorescence imaging opens a new window for the diagnosis of early-stage Alzheimer's disease.

As the global population ages, the incidence and prevalence of Alzheimer's disease (AD) continues to rise, posing a serious threat to human health. Butyrylcholinesterase (BChE), which is overexpressed in the brains of patients with AD, is a potential drug target and biomarker. However, the molecular mechanism underlying BChE's role in the AD process remains unclear. Therefore, the development of tools for BChE detection can aid in the diagnosis of AD and deepen our understanding of BChE's contribution to disease progression. Motivated by a bioinspired strategy based on the natural substrate of BChE, we designed a BChE fluorescent probe (HCYO) with a novel recognition group for BChE detection to assist in the early diagnosis of AD. This probe can selectively detect endogenous BChE with an excellent detection limit of 28.9 ng/mL. Using HCYO, we successfully imaged four-week-old mice with an ultraearly AD model, the early diagnosis of the disease. Furthermore, using this HCYO probe, we confirmed that BChE influences the inflammation-induced upregulation the levels of phosphorylated tau and Trigger Receptor Expressed on Myeloid Cells 2, impacting AD progression. These findings provide a crucial theoretical basis for the development of BChE inhibitors for AD treatment.