The Mechanism Of Aβ_1-42monomers Improving Memory In APP/PS1/Tau Tritransgenic Alzheimer’s Disease Model Mice

As a common neurodegenerative disease,the effective drug treatment of AD is still an unsolved problem in the world.In the past decades,although it is generally believed that the excessive accumulation of Aβ_1-42 is closely related to AD,the drug based on removeing Aβ_1-42 only slowed down the progression of AD and did not successfully cure the disease.In recent years,A great quantity of studies have affirmed that the production of Aβ_1-42is a normal physiological process.Although low concentrations of Aβ_1-42oligomers have neurotoxic effects,but the physiological concentrations of Aβ_1-42monomers not only play an important role in adjusting the vesicular traffic of synaptic vesicles,maintaining signal transmission and cell homeostasis but also play an important role in synaptic plasticity,learning and memory,and neuroprotection.it also has been coverd that the soluble Aβ_1-42 is reduced in cerebrospinal fluid of AD patients.Previous research in our laboratory found that the level of soluble Aβ_1-42 is reduced in cerebrospinal fluid of 9-month-old 3×Tg-AD.Based on low concentrations of Aβ_1-42oligomers have neurotoxic effects,So,is the reduction of soluble Aβ_1-42 in the brain one of the key factors leading to the development of AD?To confirm the above hypothesis,we used the behavioral techniques,vitro brain patch clamp techniques and Western blotting techniques to investigate whether adding Aβ_1-42 monomers improve the impaired memory and the potential mechanisms in 3×Tg-AD mice.The main results are as follows:1.The memory was impaired in 9-month-old 3×Tg-AD,the amplitude of s EPSC was decreased,the expression ofα7-nACh R,p-αCa MKII-Thr286,p-Glu A1（Ser831）,p-Glu A1（Ser845）and the activation of PKA/CREB/BDNF pathway in 9-month-old3×Tg-AD were significantly reduced compared to control group.2.Aβ_1-42 monomers reversed the deficits of memory,synaptic function,the expression ofα7-nACh R,p-αCa MKII-Thr286,p-Glu A1（Ser831）,p-Glu A1（Ser845）and the activation of PKA/CREB/BDNF pathway in 9-month-old 3×Tg-AD.3.MLA not only significantly inhibited the improving effects of Aβ_1-42monomers on the impaired memory,synaptic function,but inhibited the improving effects of Aβ_1-42 monomers on the expression ofα7-nACh R,p-αCa MKII-Thr286,p-Glu A1（Ser831）,p-Glu A1（Ser845）and the activation of PKA/CREB/BDNF pathway in 9-month-old3×Tg-AD mice.In conclusion,these results suggest that the decreased soluble Aβ_1-42 level in cerebrospinal fluid of 9-month-old 3×Tg-AD may be one of reasons of impaired memory,synaptic transmission function and neuroprotective pathways byα7-nACh R.Exogenous addition of soluble Aβ_1-42 monomers at low concentrations（20n M）is able to improve damaged memory in 9-month-old 3×Tg-AD mice byα7-nACh R.Our study provides a new insight into the physiological function and positive mechanism of Aβ_1-42 monomers.The findings help people to understand the pathogenesis of AD and the development of AD drugs.