The Effect Of Neuritin On Learning And Memory In Mouse Models Of Alzheimer’s Disease

Alzheimer’s disease(AD)is one of the most common neurodegenerative diseases,and the number of AD patients was as high as 47 million,which seriously threatening the physical and mental health of the old,according to the World Alzheimer Report 2018.The main clinical features of AD is cognitive dysfunction,mainly manifested by a decline of learning and memory.The accumulation of amyloid plaques in the intercellular substance,the tangles of nerve fibers in the cells and the loss of neurons with proliferation of astrocytes in the brain of AD patients ultimately lead to cognitive impairments.Studies have found that neurotrophic factors play a significant role in the growth and differentiation of synapses and neurons and the survival of neurons.It also has a crucial effect on the pathogenesis of AD.Meanwhile,it is the first step in the formation of memory that the rapid induction and expression of immediate early genes(IEGs).Neuritin is an immediate early gene that can be induced and expressed by neuronal activity,the Neuritin protein it encodes is a member of the neurotrophic factor family.Its expression is induced by synaptic activity,hormones,and seizures.It has multiple roles in neural development and synaptic plasticity,which is considered to be a common effector molecule of neurotrophic and neurotherapeutic drugs,and is closely related to learning and memory.Therefore,this article mainly explores the effect of Neuritin on the learning and memory ability of Alzheimer’s disease model mice.In this study,we first used Neuritin conditional gene knockout mice to explore the effect of knocking out Neuritin gene in neurons of whole brain on spatial exploration ability,short-term memory and long-term learning and memory of mice.Our results showed that the spatial learning ability in the knocked-out mice was impaired,indicating that the deletion of the Neuritin gene has an important connection with learning and memory impairment,and that Neuritin may have an important regulatory role on learning and memory.In order to further explore the specific cellullar mechanisms of Neuritin regulating learning and memory,we used the Cre-lox P recombinase systemmediated technology to specifically knock out the Neuritin gene in the dentate gyrus(DG)granule cell layers of hippocampus and the method of injecting Credependent Adenovirus Associated Virus(AAV)in DG of Prox1-Cre mice to analyze the effects of Neuritin expression in hippocampus-dependent learning and memory behaviors.It is found that the learning ability in mice knocked out of Neuritin gene in hippocampal granule cells show a downward trend.At the same time,compared with mice injected with control virus,the learning ability of mice injected with Neuritin overexpressing virus show an upward trend,which suggests that increased expression of Neuritin may help improve the learning and memory ability,and the regulation effect of Neuritin on learning and memory may be mainly concentrated in the hippocampal granule cell layers.Based on this,in order to further explore the effect of Neurtin on the learning and memory ability of AD model mice,we use 5×FAD mouse,APP/PS1 double transgenic mice with Alzheimer’s disease,to carry out related researches.Firstly,we tested the expression of Neuritin in the hippocampus of elderly 5×FAD mice and normal mice.The results show that the expression of Neuritin in the brain of5×FAD mice was decreased,indicating that the decrease of Neuritin is responsible for the defects of learning and memory in the brain of AD model mice.In order to specifically explore the improvement of Neuritin in learning and memory,we further injected Neuritin-overexpression virus into the hippocampal granule cell layers of 5×FAD mice to increase the expression level,and then test the learning and memory ability by multiple behavioral experiments.The results show that the learning ability of 5×FAD mice over-expressed Neuritin in the hippocampal granule cell layer reveal a slight improvement,demonstrating that Neuritin plays an important role in regulating learning and memory.In summary,Neuritin in hippocampal granule cell layers is an important regulatory protein that exerts apromoting role in the learning and memory ability.Furthermore,the results reveals that Neuritin can efficiently repair the learning defficiency of AD mouse models providing novel insights into exploring the pathogenesis of AD,and new strategies for the treatment of neurodegenerative diseases.