北京中医药大学学报2026，Vol.49Issue(8)：1043-1057,15.DOI:10.3969/j.issn.1006-2157.2026.08.002
阿尔茨海默病肾虚证小鼠模型视网膜、海马结构功能改变的动态观察研究
Dynamic changes in the structure and function of the retina and hippocampus in a mouse model of Alzheimer's disease with kidney deficiency syndrome
摘要
Abstract
Objective To dynamically assess structural and functional changes in the retina and hippocampus of a mouse model of Alzheimer's disease(AD)with kidney deficiency syndrome at different timepoints to illustrate the chronological sequence of the characteristic pathological changes in these two regions,thereby providing new insights for the early diagnosis and treatment of AD using traditional Chinese medicine.Methods To establish the AD model of kidney deficiency syndrome,the model group received AlCl3(40 mg/kg)by gavage and D-gal(120 mg/kg)by intraperitoneal injection for 14 weeks.A total of 90 male KM mice were randomly divided into model(n=45)and control groups(n=45)using the random number table method.At week 6,10,and 14 of the modeling period,15 mice were randomly selected from each group to assess behavioral changes,record food/water intake and urine output,and measure serum markers of hypothalamic-pituitary-adrenal(HPA)axis function and antioxidant capacity.Hematoxylin-eosin staining was used to examine pathological morphological changes in the hippocampus and retinal neurons;optical coherence tomography and electroretinogram(ERG)were used to assess changes in retinal structure and function;Western blot was used to detect the expression levels of Aβ1-42,P-tau,and T-tau in the retina and hippocampus;immunohistochemical staining was used to detect P-tau expression in the retina.Results Compared with the control group,the model group exhibited marked cognitive decline,reduced exploratory behavior,and anxiety-like behavior at week 14.At week 10 and 14,the model group showed reduced body weight,food intake,and water intake and increased urine output compared with the control group(P<0.05,P<0.01).At all time points,malondialdehyde levels in the model group were higher,and superoxide dismutase activity was lower than in the control group(P<0.05,P<0.01).At week 10 and 14,adrenocorticotropic hormone,corticotropin-releasing hormone and cortisol levels were elevated in the model group,whereas glutathione peroxidase activity was reduced(P<0.05,P<0.01).At week 10 and 14,morphological changes such as cell loss and disorganized arrangement were observed in the hippocampal and retinal tissues of the model group mice;the overall retinal thickness,the outer nuclear layer(ONL)thickness and cell number,and the thickness of the composite layer comprising the inner plexiform layer,ganglion cell layer(GCL),and retinal nerve fiber layer were significantly reduced in the model group(P<0.05,P<0.01);at week 14,the number of cells in the GCL and the thickness of the inner nuclear layer(INL)also significantly decreased in the model group(P<0.05,P<0.01).Under scotopic conditions with a 0.01 cd·s·m-2 flash stimulus,the a-wave amplitude in the model group was lower than that in the control group at 10 and 14 weeks(P<0.05).Under scotopic conditions with a 3.0 cd·s·m-2 flash stimulus,a significant reduction in a-and b-wave amplitudes was observed in the model group at all time points(P<0.01).Under light adaptation conditions,the amplitude of the b-wave in the model group was reduced compared with the control group at week 6,10,and 14(P<0.05,P<0.01).At week 10 and 14,the negative wave amplitude of PhNR in the model group mice was significantly reduced(P<0.05,P<0.01).In the hippocampus,P-tau/T-tau and Aβ1-42 expression levels were significantly elevated in the model group at week 14(P<0.01).At week 6,10,and 14,P-tau expression in the retina of the model group was significantly increased(P<0.01),with positive staining primarily observed in the GCL,INL,and ONL;however,Aβ1-42 protein expression showed no significant difference at any time point.Conclusion In the AD mouse model with kidney deficiency syndrome,abnormalities in retinal structure and function,as well as abnormal expression of P-tau,occurred earlier than the hippocampal AD-like pathological changes and cognitive dysfunction.The abnormal deposition of P-tau in the GCL,INL,and ONL may be the key factor causing structural and functional damage to the retina.This finding may provide novel insights for the early diagnosis and treatment of AD with kidney deficiency syndrome.关键词
阿尔茨海默病/视网膜/磷酸化tau蛋白/肾虚证/小鼠Key words
Alzheimer's disease/retina/phosphorylated tau/kidney deficiency syndrome/mice分类
医药卫生引用本文复制引用
李丹阳,艾民,黄雨,周派,李书楠,彭清华..阿尔茨海默病肾虚证小鼠模型视网膜、海马结构功能改变的动态观察研究[J].北京中医药大学学报,2026,49(8):1043-1057,15.基金项目
国家自然科学基金项目(No.82505673,No.81874492) National Natural Science Foundation of China(Nos.82505673 and 81874492) （No.82505673,No.81874492）
