Working Memory Ameliorated With Engineered Bacterium Escherichia Coli Nissle 1917-GLP-1 In The Aged Monkeys

Working memory(WM)refers to an individual’s ability to extract and manipulate taskrelated stored information in the brain and stimuli environment during the execution of complex behaviors.As a core component of brain higher cognitive function dependent on the prefrontal cortex,WM is used to guide the successful completion of behaviors.The decline of cognitive function represented by WM impairment is the biggest difficulty encountered by the elderly,leading to the decline of individual quality of life,which is a social problem to be solved urgently.Glucagon-like Peptide 1(GLP-1)is an endogenous hormone composed of 30 amino acids that binds to GLP-1 receptors in the gut to promote insulin secretion.Studies have shown that GLP-1 analogues improve cognitive function in patients with diabetes and obesity.However,GLP-1 has a very short half-life,which limits its clinical application.It is a new path worth exploring to develop new biotechnology to increase the continuous secretion of endogenous GLP-1and prolong the action time of GLP-1,to achieve the purpose of improving cognitive function.Our previous work used genetic engineering to construct an engineered bacterium Escherichia coli Nissle 1917-GLP-1(Ec N-GLP-1),which not only expresses and secretes GLP-1 into the extracellular space,but also has neuroprotective effects on a mouse model of degenerative disease.However,whether the engineered bacterium Ec N-GLP-1 can improve cognitive function in primates has not been reported.In this study,elderly macaques(Macaca mulatta)were administered orally with Ec N-GLP-1 to detect whether GLP-1 levels were elevated in the monkeys and to observe whether performance of WM related behavioral tasks was improved.The results were as follows: 1.After administering of Ec N-GLP-1,GLP-1 content in feces and serum was significantly increased.2.After oral Ec N-GLP-1,the performance of monkey spatial delayed matching-to-sample task was significantly improved.We provide direct behavioral evidence that specific probiotic supplements can serve as a non-pharmacological intervention for cognitive enhancement in primates,opening new avenues for improving WM in older adults.