Ursolic acid reduces Aβ-driven aggression via Gab1-mediated autophagy and dorsal hippocampal circuit modulation in Alzheimer’s disease

INTRODUCTION: Aggression is one of the most debilitating neuropsychiatric symptoms in Alzheimer's disease (AD), posing significant challenges for both patients and caregivers. However, the underlying mechanism remains unclear, and effective therapeutic strategies are lacking. OBJECTIVES: This study aimed to investigate the neural circuit mechanisms underlying amyloid-beta (Aβ)-driven aggression in AD and explore the therapeutic potential of ursolic acid (UA) in alleviating this behavior. METHODS: A combination of virus tracing, electrophysiological recording, in vivo Ca2 + recording, and a aggressive behavior test was utilized to investigate the neural circuit vulnerable to Aβ-driven aggression. optogenetic or chemogenetic manipulation was used to identify the regulation of the neural circuit on aggressive behavior. Proteomics and molecular targeting were employed to explore the underlying mechanisms of Aβ-driven aggression and evaluate UA's effects. RESULTS: We identified that Aβ accumulation drove hyperexcitability of dorsal hippocampal CA3 (dCA3) neurons projecting to the dorsal lateral septum (dLS), thereby triggering aggressive behavior in the 5xFAD mouse model. Optogenetic activation of the dCA3-dLS circuit in wild-type mice induced aggression, whereas either optogenetic or chemogenetic inhibition of this projection alleviated aggression in 5xFAD animals. Proteomic profiling of dCA3 tissue identified Grb2-associated binding protein 1 (Gab1) as a key mediator upregulated in 5xFAD mice and normalized by ursolic acid (UA) treatment. UA reduced Aβ plaque burden, restored autophagic flux (increasing LC3B-II and decreasing p62), and suppressed dCA3-dLS circuit hyperactivity, resulting in durable attenuation of aggressive behavior. Viral knockdown of Gab1 in dCA3 mimicked UA's effects on autophagy, Aβ clearance, circuit excitability, and aggression, whereas Gab1 overexpression blocked UA's benefits. CONCLUSION: Together, these results define a novel Gab1-dependent autophagy-circuit mechanism for Aβ-induced aggression and establish UA as a promising candidate for alleviating neuropsychiatric symptoms in AD.