Photocontrollable Electrochemical Molecular Probe for the Detection of Cu2+ in Brain Dialysates of Alzheimer's Disease Mice.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is closely associated with the dyshomeostasis of copper ions (Cu2+) in the brain. Aberrant cerebral Cu2+ accumulation induces the aggregation of amyloid-β peptides and the generation of reactive oxygen species, which represent the key pathological hallmarks of AD. Herein, we report a photocontrollable electrochemical molecular probe (TPMP) for the highly selective and sensitive detection of Cu2+ in the brain dialysates of AD model mice. TPMP is rationally engineered with three core functional moieties: a 2-nitrobenzyl group as the photolabile unit, hydroquinone (HQ) as the electroactive reporter, and picolinate as the Cu2+ recognition group. In the dark, the specific binding of Cu2+ to the picolinate moiety of TPMP triggers the hydrolytic cleavage of picolinate, yet this reaction only yields a stable reaction intermediate without the release of electrochemically active HQ, thus rendering the probe in an electrochemically silent state with no detectable electrochemical signal. Only upon subsequent irradiation with 365 nm ultraviolet (UV) light does the 2-nitrobenzyl photolabile group in the intermediate undergo irreversible photolytic cleavage, which enables the quantitative release of free electroactive HQ and thereby produces a distinct turn-on electrochemical response for the specific detection of Cu2+. The probe exhibits excellent analytical performance, including high selectivity against coexisting interfering metal ions and biological molecules and favorable sensitivity with a limit of detection of 30 nM. Furthermore, TPMP has been successfully applied for the accurate quantification of Cu2+ in the brain dialysates of AD model mice, validating its practicability and reliability in complex biological matrices. This photocontrollable sensing strategy achieves sequential Cu2+ recognition and light-triggered signal activation, which effectively eliminates nonspecific interference from complex biological samples and provides a promising analytical tool for investigating Cu2+-mediated pathological processes in AD. It also offers a novel design strategy for the development of photocontrollable electrochemical probes for the early diagnosis of AD and other metal ion-related neurodegenerative diseases.