Alzheimer's disease (AD) is a progressive neurodegenerative condition with complex causes. Despite extensive research, effective disease-modifying treatment options remain limited. Recent studies have indicated that hydrogen molecule (H2) possesses therapeutic potential for AD, and it is of vital importance to enhance the bioavailability of H2 in the gastrointestinal tract based on the gut-brain axis. In this work, we develop iron boride nanostructures (FBN) as a novel acid-responsive hydrogen-releasing material with a high hydrogen release capacity to enhance the H2 delivery efficacy towards the gastrointestinal tract for AD treatment. In male 5×FAD and 3×Tg-AD mice, oral FBN administration generated H2 under gastric conditions and was associated with AD-like behavioral and pathological improvements, including improved learning and memory and attenuation of neuronal and synaptic damage. FBN treatment was associated with increased synaptophysin (SYP) expression and dendritic spine density. Additionally, FBN treatment was associated with reduced amyloid-beta (Aβ) accumulation and attenuated tau pathology, two key pathological features of AD. FBN treatment was also associated with increased expression of mitochondrial fusion-related proteins and improved mitochondrial morphology. Furthermore, FBN treatment increased antioxidant defense-related proteins and reduced apoptosis-related markers, suggesting a possible enhancement of neuroprotective responses. In addition, FBN treatment induced changes in gut microbiota-related metabolites, suggesting a possible contribution of the gut-brain axis. These findings provide valuable insight into the mechanisms underlying the protective effects of hydrogen against AD and support the development of hydrogen-based therapies for slowing or preventing disease progression.
