Revealing Formaldehyde Fluxes in Alzheimer's Disease Brain by an Activity‐Based Fluorescence Probe

Comprehensive Summary Formaldehyde (FA) plays critical roles in Alzheimer's disease and the associations between FA and Alzheimer's disease (AD) are still obscure. To reveal FA fluxes in the Alzheimer's disease brain, an activity‐based fluorescence probe NP‐FA with superb blood‐brain barrier permeable abilities was exquisitely designed. The probe responded to FA with significant fluorescence increases ( F / F 0 = 81), thus laying the foundation for the sensitive detection of FA in cuvette and in vivo . Moreover, the probe also possessed some fascinating performances, including endoplasmic reticulum (ER)‐targeting abilities, good one‐photon/two‐photon absorption properties, and appropriate hydrophobicity property (log P = 2.34 ± 0.05). As a result, the probe can readily reflect the overproduction of FA content in live cells under ER stress by high‐fidelity two‐photon imaging. More interestingly, ex vivo imaging of AD brains and two‐photon imaging of AD slice tissues visually disclosed that the FA level of AD brain is much higher than that of the normal brain. This work afforded a specific activity‐based probe for the imaging of FA in the AD mouse brains, which could be further extended to FA‐related studies in Alzheimer's disease.