Modified Kaixin San improves memory and synaptic damage of mice with Alzheimer's disease by modulating αCaMKⅡ-PSD95 protein binding through inhibition of neuroinflammation:a study of mechanism.
10.19540/j.cnki.cjcmm.20220704.501
- Author:
Zhi-Yuan LU
1
;
Chen-Yi ZHAO
1
;
Guang YANG
1
;
Yu-Ting TONG
1
;
Zong-Tao BA
1
;
Ahelijiang REAILA
1
;
Jian-Mei YANG
2
;
Ying XU
1
Author Information
1. Department of Physiology,Shanghai University of Traditional Chinese Medicine Shanghai 201203,China.
2. Department of Traditional Chinese Medicine,Shanghai Xuhui District Central Hospital Shanghai 200031,China.
- Publication Type:Journal Article
- Keywords:
Alzheimer′s disease(AD);
PS cDKO mouse;
memory impairment;
modified Kaixin San;
neuroinflammation;
synaptic damage
- MeSH:
Animals;
Mice;
Alzheimer Disease/genetics*;
Disks Large Homolog 4 Protein/metabolism*;
Neuroinflammatory Diseases;
Tumor Necrosis Factor-alpha/metabolism*;
Cyclooxygenase 2/metabolism*;
Interleukin-6/metabolism*;
Protein Binding;
Mice, Knockout;
Hippocampus/metabolism*;
Disease Models, Animal;
RNA, Messenger/metabolism*
- From:
China Journal of Chinese Materia Medica
2022;47(22):6217-6226
- CountryChina
- Language:Chinese
-
Abstract:
To investigated the mechanisms underlying the effects of modified Kaixin San(MKXS) on improving memory and synaptic damage of Alzheimer's disease(AD) mouse model with conditional presenilin 1/2 conditional double knockout(PS cDKO). Specifically, 60 PS cDKO mice(3-3.5 months old) and their age-matched wild-type(WT) littermates were randomized into three groups: WT group(n=20), PS cDKO group(n=20), and PS cDKO+MKXS group(n=20). Mice in WT and PS cDKO groups were fed with standard chow and those in PS cDKO+MKXS group were given chow containing MKXS(at 2.55 g·kg~(-1)) for 60 days. Novel object reco-gnition task was employed to detect the recognition memory of mice, and Western blot to detect the protein levels of synapse-associated proteins in the hippocampus(HPC) of mice, such as NR1, NR2 A, NR2 B, p-αCaMKⅡ, tau, and p-tau. Microglial morphology in the HPC CA1 of mice was observed based on immunohistochemistry. Quantitative real time-PCR(qRT-PCR) was employed to detect the mRNA levels of the pro-inflammatory factors and synapse-associated proteins in the HPC of mice, including COX-2, iNOS, IL-1β, IL-6, TNF-α, PSD95, NR1, NR2 A, NR2 B, and MAP2. The protein levels of IL-1β, TNF-α, and IL-6 were tested by enzyme-linked immunosorbent assay(ELISA). The interaction between PSD95 and αCaMKⅡ and between PSD95 and p-αCaMKⅡ was tested by co-immunoprecipitation(Co-IP). The results showed that PS cDKO+MKXS demonstrated significantly higher preference index and recognition index of the new objects, lower protein level of p-tau(ser 396/404) and mRNA levels of COX-2, iNOS, TNF-α, IL-1β, and IL-6 in HPC, higher protein levels of NR1, NR2 A, NR2 B, and p-αCaMKⅡ and mRNA levels of NR1, NR2 A, NR2 B, PSD95, and MAP2, and stronger interaction of αCaMKⅡ with PSD95 and interaction of p-αCaMKⅡ with PSD95 than the PS cDKO group. Immunohistoche-mical staining showed that MKXS inhibited the activation of microglia. In conclusion, MKXS improves memory and synaptic damage in mice with AD by modulating αCaMKⅡ-PSD95 protein binding through inhibition of neuroinflammation.
