KaiXinSan improves learning and memory impairment by regulating cholesterol homeostasis in mice overloaded with 27-OHC

Cholesterol and its oxidative products—oxysterols homeostasis— play a crucial role in maintaining cognitive function. Chinese medicine KaiXinSan (KXS) has demonstrated effectiveness in treating mental illness and regulating cognitive dysfunction of Alzheimer's disease (AD). The purpose of this article is to explore whether the KXS can enhance cognitive function by regulating cholesterol homeostasis. Employing the 27-hydroxy cholesterol (27-OHC) induced mice model of cognitive dysfunction and coculture model of assessment neurocyte damage, we investigated learning and memory abilities while concurrently addressing the reduction of neuronal cell damage through the regulation of cholesterol metabolism. 21 days of KXS treatment improved the learning and memory ability in mice 27-OHC-overloading by alleviating the exacerbated deposition of amyloid-β (Aβ), reducing inflammatory reactions, and mitigating synaptic plasticity damage. Additionally, it repaired myelin sheath function. More importantly, KXS significantly affects the metabolism of central cholesterol by substantially inhibiting the expression of liver X receptor (LXR), ATP-binding cassette transporter (ABCA1, ABCG1), apolipoprotein E (ApoE) and upregulated cytochrome P450 46A1(CYP46A1). Furthermore, KXS may alleviate 27-OHC-induced neuronal inflammation and apoptosis by promoting the conversion of cholesterol to 24-hydroxycholesterol (24-OHC) via CYP46A1 and suppressing cholesterol release from astrocyte cells. Altogether, our results demonstrate that KXS can prevent learning and memory impairments induced by 27-OHC loading. This effect may be related to its multitarget capability in promoting the conversion of excessive cholesterol to 24-OHC and maintaining a balance in cholesterol homeostasis and metabolism between neurons and astrocyte cells.