The Mechanism Of Aβ_1-42 Monomers Or Aβ_1-15 Improving Memory In APP/PS1/Tau Transgenic AD Mice

BackgroundAlzheimer’s disease（AD）is a common progressive neurodegenerative disorder.The economic burden of AD on families and society will surpass that of heart disease and cancer in the future.There is still a lack of effective treatment for AD,and a new approach is urgently needed.Amyloidβ-protein（Aβ）deposition is one of the most prominent pathological features of AD.However,drug development based on the Aβcascade hypothesis has failed to reverse the progression of AD deterioration.Under normal physiological conditions,endogenous Aβ_1-42produced by healthy brain plays an indispensable role in learning and memory and synaptic plasticity,and its hydrophilic N-terminal region Aβ_1-15is a key fragment for its role.Clinical data showed that the level of soluble Aβ_1-42in cerebrospinal fluid（CSF）decreased in AD patients,suggesting that the occurrence of AD symptoms may be related to the decrease of soluble Aβ_1-42monomer.Aβ_1-42has a very high affinity and interaction withα7-nicotinic acetylcholine receptor（α7-n ACh R）in the hippocampus of AD patients.Moreover,the protein level ofα7-n ACh R significantly decreased in the hippocampus of AD patients.Therefore,we speculate that the reduction of soluble Aβ_1-42monomer lead to the decreased level ofα7-n ACh R may be one of the causes of AD,which involved in learning and memory,synaptic plasticity,and neuroprotective pathway.We used 3×Tg-AD mice to explore the level of soluble Aβ_1-42in the CSF of 3×Tg-AD mice with age,through behavioral,electrophysiological,and molecular experiments.And we investigated whether adding Aβ_1-42monomers（20 n M）and Aβ_1-15（500 n M）improve the deficits of cognition,synaptic plasticity and neuroprotective pathway in the hippocampus of 3×Tg-AD mice.Methods and Results1.The result of ELISA experiment showed that the level of soluble Aβ_1-42in the CSF of 9-month-old 3×Tg-AD mice was significantly lower than that of 3-month-old3×Tg-AD mice.Western blotting showed that the level of synapticα7-n ACh R in the hippocampal region of 3×Tg-AD mice at 9 months of age was significantly decreased compared to control group.2.The results of spontaneous Y maze and novel location recognition tasks showed that Aβ_1-42monomers or Aβ_1-15improved the spatial working and novel location recognition dysfunctions in 9-month-old 3×Tg-AD mice.3.Consistent with the behavioral results,Aβ_1-42monomers or Aβ_1-15improved the deficits of synaptic plasticity in 9-month-old 3×Tg-AD mice in electrophysiological experiments.4.To further explore the molecular mechanisms by which either Aβ_1-42monomers or Aβ_1-15could improve learning and memory and synaptic plasticity,we found that Aβ_1-42monomers or Aβ_1-15could improved the decreasing levels inα7-n ACh R,p Glu N2B-Tyr1472,p Glu A1-Ser831,p Glu A1-Ser845 and the activation of PI3K/AKT/GSK-3βpathway in 9-month-old 3×Tg-AD by using western blotting experiments.5.By adding an antagonist ofα7-n ACh R methyllycaconitine citrate（MLA）,we foundα7-n ACh R mediated the improved effect of Aβ_1-42monomers or Aβ_1-15on impaired memory,synaptic plasticity and neuroprotection in 3×Tg-AD mice.ConclusionTaken together,these results suggest that the decreased soluble Aβ_1-42level in CSF of 9-month-old 3×Tg-AD mice may cause the impaired synaptic plasticity and memory through decreasing the levels of synapticα7-n ACh R,p Glu N2B-Tyr1472,p Glu A1-Ser831,p Glu A1-Ser845 as well as the activation of PI3K/AKT/GSK-3βpathway.Aβ_1-42monomers or Aβ_1-15improves impaired memory,synaptic plasticity,and neuroprotective pathways,which may be mediated byα7-n ACh R in 9-month-old3×Tg-AD mice.We propose that the reduction of soluble Aβ_1-42monomers in CSF may be one of the important causes of the impaired cognition in 9-month-old 3×Tg-AD mice.These findings provide a novel insight into the mechanism of memory and synaptic plasticity dysfunction in AD and the development of anti-AD drugs.