In Situ Fluorescence Imaging Reveals Contribution of Cerebral Hydroxyl Radicals in Hyperhomocysteinemia-Induced Alzheimer-like Dementia

Abstract

Elevated plasma level of homocysteine, also termed as hyperhomocysteinemia, is acknowledged as a significant and independent risk factor of Alzheimer's disease. However, the mechanistic insight has not been thoroughly elucidated yet. In this work, 3,5-dihydroxybenzyloxy was explored as the unique reaction trigger and integrated into the naphthalimide fluorophore via a carbamate linker to afford a new probe for • OH imaging. • OH treatment induced aromatic hydroxylation and subsequent elimination reaction to release the caged fluorophore, accompanied with a highly specific and sensitive turn-on fluorescence response. Cell imaging results revealed that excess homocysteine triggered overwhelming • OH production, which was mediated by N-methyl-Daspartate receptor and NADPH oxidase, and the resultant • OH stress further initiated neuronal ferroptosis, also confirmed by western blot analyses. Additionally, hyperhomocysteinemic mouse models were established, and Alzheimer-like dementia of the mice was observed from behavioral tests. Most importantly, with this probe, cerebral • OH fluctuation was in situ visualized in live mice, which positively correlated with the severity of Alzheimer-like dementia induced by hyperhomocysteinemia. These results reveal that cerebral • OH stress may be the critical nexus linking hyperhomocysteinemia and Alzheimer's disease. This work provides a robust fluorescence probe for in situ visualizing the cerebral • OH fluctuations and illuminating critical insights into • OH contributions in brain disorders.

Visualization of Acrolein Upregulation during Ferroptosis by a Ratiometric Fluorescent Probe

“…Moreover, the fluorescence intensity ratio has a very satisfactory linear relationship with ACR concentration ( y = 0.0402 × [ACR] (μM) + 0.7632, R 2 = 0.9907). The detection limit of 0.26 μM was also obtained by the calculated equation of 3σ/k. , Obviously, probe HBT-SH possesses higher sensitivity and accuracy for monitoring ACR compared with most reported ACR fluorescent probes.…”

Monitoring Alzheimer’s disease via ultraweak photon emission

“…This advantage stems from the fact that oxidative stress, a precursor to AD, occurs at an earlier stage, and the UPE signals possess the capability to robustly detect this early sign. There are several approaches (e.g., MRI, PET, and fluorescence imaging 88 , 89 , 90 ) applied for AD detection and diagnosis with noninvasiveness and in vivo imaging capability. However, the above imaging methods are reliant on relatively costly, intricate, and stationary devices, often necessitating the injection of contrast agents during certain detection processes.…”