Effects Of Sodium Propionate On Aβ-induced Cognitive Function In Mice With Alzheimer’s Disease And Its Mechanism

ObjectiveAlzheimer’s disease is the most common form of senile dementia,and its pathological results have a serious impact on human life.Therefore,it is of great importance to explore how to improve the learning and memory ability of alzheimer’s patients.Currently,several drugs approved by the US Food and Drug Administration to treat AD,such as memantine and Donepezil,can only slow the progression of AD,but not stop it.Therefore,this study investigated the effects of sodium propionate on the learning and memory ability and cognitive behavior of AD mice induced by Aβ_1-42,and analyzed the possible mechanism,to provide theoretical basis for clinical treatment of Alzheimer’s disease patients.Methods1.Male 6-week-old ICR mice weighing 25～30g were randomly divided into sham operation group,Aβ_1-42group,Aβ_1-42+SP50mg/kg group,Aβ_1-42+SP100mg/kg group,and Aβ_1-42+SP200mg/kg group.2.After one week of adaptive feeding,all mice were injected into the lateral ventricle.The sham operation group was given 3μL normal saline,and the other groups were given Aβ_1-42to establish acute AD model.3.Sodium propionate treatment group were given 50mg/kg,100mg/kg and200mg/kg sodium propionate for intraperitoneal injection,respectively.The sham operation group and AD group were given normal saline.The hippocampus and frontal cortex of mice were collected after 21 days of administration once a day.4.The new object recognition experiment and Morris water maze behavior experiment（positioning navigation experiment and space exploration experiment）were used to test the cognition,learning and memory ability of mice.5.The concentrations of inflammatory cytokines IL-1β,TNF-α,IL-4 and IL-10 in the frontal cortex of mice were determined by ELISA.6.Western blot and immunofluorescence were used to detect the expression of SYN and PSD95,as well as inos,a M1-type microglia marker.Results1.New object recognition experiment results:In the test phase,the Aβ_1-42group was poorer at recognizing new and familiar objects than the sham group（p<0.001）.Compared with Aβ_1-42group,sodium propionate 100mg/kg（p<0.05）and 200mg/kg（p<0.05）groups significantly increased the discrimination index.2.Morris water maze results:Compared with the sham operation group,mice in the Aβ_1-42group spent longer time searching for the platform（p<0.001）,crossed the platform less times（p<0.001）,and target quadrant swim time reduced（p<0.001）.Compared with Aβ_1-42group,sodium propionate 100mg/kg and 200mg/kg groups significantly reduced escape latency（p<0.001）,increased platform crossing times（100mg/kg,p<0.05,200mg/kg,p<0.001）and target quadrant swimming time（100mg/kg,p<0.01;200mg/kg,p<0.001）.3.Effect of sodium propionate on neuroinflammation:Compared with thesham operation group,the expression levels of IL-1β（p<0.001）and TNF-α（p<0.05）increased in the Aβ_1-42group.Compared with Aβ_1-42group,the expression of IL-1βdecreased in the 100mg/kg sodium propionate group（p<0.01）and the 200mg/kg sodium propionate group（p<0.001）,and the expression of TNF-αdecreased in the200mg/kg sodium propionate group（p<0.05）.Compared with the sham operation group,the expression levels of IL-4（p<0.01）and IL-10（p<0.001）decreased in Aβ_1-42group,and increased in 200mg/kg sodium propionate group compared with Aβ_1-42group（p<0.05）.The expression of IL-10increased in the 100mg/kg sodium propionate group（p<0.01）and the 200mg/kg sodium propionate group（p<0.001）.4.Effect of sodium propionate on inducible nitric oxide synthase:Compared with the sham operation group,i NOS fluorescence positive substance was stronger in Aβ_1-42group（p<0.01）,and the fluorescence intensity of sodium propionate 200mg/kg group was weaker than that of Aβ_1-42group（p<0.01）.Western Blot results showed that the expression of i NOS protein in Aβ_1-42group was higher than that in the control group（p<0.05）.Compared with Aβ_1-42group,the expression of i NOS protein in 200mg/kg sodium propionate group was lower than that in Aβ_1-42group（p<0.05）.5.Effects of sodium propionate on marker proteins of synaptic plasticity:C ompared with the sham operation group,the fluorescence intensity of SYN fluor escence-positive substances in Aβ_1-42group was lower（p<0.001）,and the fluores cence intensity of SYN fluorescence-positive substances in 200mg/kg sodium pro pionate group was more dense（p<0.01）.Western Blot results showed that the le vel of SYN protein in Aβ_1-42group was lower than that in the control group（p<0.05）,and the level of SYN protein in 200mg/kg sodium propionate group was higher than that in Aβ_1-42group（p<0.05）.Immunofluorescence microscopy showed that PSD95 fluorescence positive substances were weaker in the Aβ_1-42group than in the sham group（p<0.001）.Compared with Aβ_1-42group,the fluorescence intensity of PSD95 positive substances was denser in 200mg/kg sodium propionate group（p<0.001）.Western Blot results showed that compared with the control group,PSD95 protein level was lower in Aβ_1-42group（p<0.05）,and PSD95 protein level was increased in 200mg/kg sodium propionate group compared with Aβ_1-42group（p<0.05）.ConclusionAβ_1-42induced decline in cognition,learning and memory in alzheimer’s disease mice.Sodium propionate 200mg/kg can significantly improve the cognitive dysfunction of Aβ_1-42mice.The possible mechanism is that sodium propionate up-regulated the expression of anti-inflammatory factors IL-4 and IL-10,down-regulated the expression of pro-inflammatory factors IL-1βand TNF-α,and then decreased the level of i NOS,the microglia marker,and enhanced the expression of synaptic plasticity markers,thus improving the cognitive learning ability of AD mice.