HMGB1 Box A gene therapy reverses cognitive and neuropathological features in AlCl₃/D-galactose rat model of Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, is pathologically defined by the accumulation of amyloid-β and tau pathology, resulting in progressive cognitive decline. Our previous work demonstrated that high mobility group box 1 (HMGB1) Box A plasmids alleviated cellular senescence and restored cognitive performance in aged rat models, supporting their therapeutic potential for neurodegenerative disorders such as AD. In this study, we investigated the efficacy of HMGB1 Box A gene therapy in an AD-like rat model chronically induced by AlCl3 and D-galactose. Following the onset of AD pathology, Box A plasmids were administered weekly at varying doses over eight weeks. Box A treatment significantly improved behavioral outcomes, including responsiveness, locomotor activity, and learning and memory performance. At the neuropathological level, Box A reduced hippocampal Aβ accumulation and tau pathology, restored neuronal density, and attenuated synaptic degeneration. Moreover, it suppressed hippocampal microgliosis, astrogliosis, and the expression of proinflammatory mediators. Box A also diminished markers of cellular senescence in the hippocampus. These findings demonstrate that HMGB1 Box A gene therapy confers multi-level neuroprotective effects in AD, from molecular and cellular restoration to behavioral recovery. This strategy holds strong promise as a disease-modifying treatment for AD, contributing to improved well-being by advancing therapeutic innovation to promote healthy aging and combat age-related neurodegenerative diseases.