Abstract:Objective: To investigate the effects of serum uric acid levels on cognitive function and Aβ expression in hippocampus of rats, and to explore the related mechanisms. Methods: Twentyfour Wistar male rats were randomly divided into control group, lowdose model group, middledose model group and highdose model group, with 6 rats in each group. The hyperuricemia animal model was established by using yeast extract feed combined with different concentrations of potassium oxonate intraperitoneal injection for 4 weeks. The learning and memory ability of the rats in each group was tested by Morris water maze. The expression levels of Aβ and key proteins in Aβ production and clearance pathways in the hippocampus of rats in each group were detected by ELLISA and Western blotting assays. Results: Compared with the control group, the level of uric acid in each model group was significantly increased (P<0.01). And there was no significant difference in the number of times of crossing the platform and the time spent in the quadrant of the platform in each group. Compared with control group, the expression levels of Aβ142, amyloid precursor protein (APP), βsite APP cleaving enzyme 1 (BACE1), neprilysin (NEP) and insulin degrading enzyme (IDE) were increased in model groups, and the expression levels increased with the raise of serum uric acid level. However, the expression of ABCG2 was decreased in model group, and gradually decreased with the increase of serum uric acid level. Conclusion: Hyperuricemia can aggravate Aβ deposition in rat hippocampus, possibly through the APPBACE1 pathway to increase the production of Aβ or/and the ABCG2 pathway to reduce the clearance of Aβ, rather than through NEP, IDE degradation pathways. Hyperuricemia had no significant effect on cognitive function.
[1]Gupta MK, Singh JA. Cardiovascular disease in gout and the protective effect of treatments including uratelowering therapy[J]. Drugs, 2019, 79(5): 531-541.
[2]Desideri G, Gentile R, Antonosante A, et al. Uric acid amplifies Aβ amyloid effects involved in the cognitive dysfunction/dementia: evidences from an experimental model in vitro[J]. J Cell Physiol, 2017, 232(5): 1069-1078.
[3]Pan SY, Cheng RJ, Xia ZJ, et al. Risk of dementia in gout and hyperuricaemia: a metaanalysis of cohort studies[J]. BMJ Open, 2021, 11(6): e041680.
[4]Qiao M, Chen C, Liang Y, et al. The influence of serum uric acid level on Alzheimer′s disease: A narrative review[J]. Biomed Res Int, 2021, 2021: 5525710.
[5]Suzuki K, Koide D, Fujii K, et al. Elevated serum uric acid levels are related to cognitive deterioration in an elderly Japanese population[J]. Dement Geriatr Cogn Dis Extra, 2016, 6(3): 580-588.
[6]Alam AB, Wu A, Power MC, et al. Associations of serum uric acid with incident dementia and cognitive decline in the ARICNCS cohort[J]. J Neurol Sci, 2020, 414: 116866.
[7]Wang Z, Meng L, Shen L, et al. Impact of modifiable risk factors on Alzheimer′s disease: A twosample Mendelian randomization study[J]. Neurobiol Aging, 2020, 91: 167. e11-167. e19.
[8]Li LL, Ma YH, Bi YL, et al. Serum uric acid may aggravate Alzheimer′s disease risk by affecting amyloidosis in cognitively intact older adults: The CABLE Study[J]. J Alzheimers Dis, 2021, 81(1): 389-401.
[9]刘睿, 王伟, 殷小平. 不同水平血尿酸对大鼠学习记忆能力的影响[J]. 山东医药, 2017, 57(22): 33-35.
[10]Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory[J]. Nat Protoc, 2006, 1(2): 848-858.
[11]Kanellis J, Watanabe S, Li JH, et al. Uric acid stimulates monocyte chemoattractant protein1 production in vascular smooth muscle cells via mitogenactivated protein kinase and cyclooxygenase2[J]. Hypertension, 2003, 41(6): 1287-1293.
[12]马思飞, 郭美娜, 刘文君, 等. 自噬调控与阿尔茨海默病相关的分子机制研究进展[J]. 江苏大学学报(医学版), 2021, 31(2): 120-123, 128.
[13]Soldan A, Pettigrew C, Cai Q, et al. Hypothetical preclinical Alzheimer disease groups and longitudinal cognitive change[J]. JAMA Neurol, 2016, 73(6): 698-705.
[14]Wang YJ, Zhou HD, Zhou XF. Clearance of amyloidbeta in Alzheimer′s disease: progress, problems and perspectives[J]. Drug Discov Today, 2006, 11(19/20): 931-938.