Sulforaphane improved cognitive behavior in APP/PS1 mice via promoting structural and functional synaptic plasticity in the hippocampus.

Abstract

Cognitive dysfunction is the main clinical feature of Alzheimer's disease (AD), and oxidative stress is considered a critical contributor to AD pathogenesis. Sulforaphane (SFN), an aliphatic isothiocyanate predominantly derived from cruciferous vegetables, has been reported to exert antioxidant and neuroprotective effects; however, its impact on synaptic plasticity and the underlying electrophysiological mechanisms in AD remain unclear. In this study, ten-month-old male APPswe/PS1dE9 double transgenic (APP/PS1) mice and wild-type (WT) littermates were randomized to four groups (WT + saline, WT + SFN, APP/PS1 + saline, and APP/PS1 + SFN). SFN was administered at 10 mg kgvia intraperitoneal injection for 30 d in vivo and 1 μM concentration in vitro. Then, we investigated whether SFN improves cognition by restoring hippocampal synaptic plasticity in APP/PS1 mice. It was suggested that SFN administration significantly attenuated Aβ₁₋₄₂-induced oxidative damage in vitro and improved spatial learning and reference memory deficits in APP/PS1 mice. Bioinformatics analysis suggested that SFN modulated synapse-related pathways associated with AD. Consistent with these findings, electrophysiological recordings demonstrated that SFN alleviated hippocampal long-term potentiation (LTP) impairment. Moreover, SFN increased the expression of synaptic proteins PSD-95 and synaptophysin and enhanced dendritic complexity and dendritic spine density in the hippocampal CA1 region, as assessed by immunoblotting and Golgi staining. Together, these results indicated that SFN ameliorated cognitive deficits in AD mice by alleviating LTP inhibition and restoring synaptic structural integrity, supporting a role for synaptic plasticity in the neuroprotective effects of SFN.